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HAEM5:Immunoglobulin-related (AL) amyloidosis (view source)
Revision as of 14:18, 3 November 2023
, 14:18, 3 November 2023Created page with "{{DISPLAYTITLE:Immunoglobulin-related (AL) amyloidosis}} Haematolymphoid Tumours (5th ed.) {{Under Construction}} <blockquote class='blockedit'>{..."
{{DISPLAYTITLE:Immunoglobulin-related (AL) amyloidosis}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
{{Under Construction}}
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. The original page can be found at [[HAEM4:Primary Amyloidosis]].
}}</blockquote>
==Primary Author(s)*==
Heather E. Williams, PhD, MS, PgD, ErCLG
__TOC__
==Cancer Category/Type==
Mature B-cell neoplasms
==Cancer Sub-Classification / Subtype==
Monoclonal immunoglobulin deposition disease
==Definition / Description of Disease==
*A member of the group of “monoclonal immunoglobulin deposition diseases” that are characterized by visceral and soft tissue deposition of aberrant immunoglobulin (Ig), which subsequently results in organ dysfunction<ref>{{Cite journal|last=Aucouturier|first=Pierre|last2=Khamlichi|first2=Ahmed A.|last3=Touchard|first3=Guy|last4=Justrabo|first4=Eve|last5=Cogne|first5=Michel|last6=Chauffert|first6=Bruno|last7=Martin|first7=Francois|last8=Preud'homme|first8=Jean-Louis|date=1993|title=Heavy-Chain Deposition Disease|url=http://www.nejm.org/doi/abs/10.1056/NEJM199311043291905|journal=New England Journal of Medicine|language=en|volume=329|issue=19|pages=1389–1393|doi=10.1056/NEJM199311043291905|issn=0028-4793}}</ref><ref>{{Cite journal|last=J|first=Buxbaum|date=1992|title=Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease|url=https://pubmed.ncbi.nlm.nih.gov/1582976/|language=en|pmid=1582976}}</ref><ref>{{Cite journal|last=Herzenberg|first=Andrew M.|last2=Lien|first2=John|last3=Magil|first3=Alex B.|date=1996|title=Monoclonal heavy chain (immunoglobulin G3) deposition disease: report of a case|url=https://linkinghub.elsevier.com/retrieve/pii/S0272638696901419|journal=American Journal of Kidney Diseases|language=en|volume=28|issue=1|pages=128–131|doi=10.1016/S0272-6386(96)90141-9}}</ref><ref>{{Cite journal|last=Kambham|first=Neeraja|last2=Markowitz|first2=Glen S.|last3=Appel|first3=Gerald B.|last4=Kleiner|first4=Morton J.|last5=Aucouturier|first5=Pierre|last6=D'Agati|first6=Vivette D.|date=1999|title=Heavy chain deposition disease: The disease spectrum|url=https://linkinghub.elsevier.com/retrieve/pii/S0272638699704324|journal=American Journal of Kidney Diseases|language=en|volume=33|issue=5|pages=954–962|doi=10.1016/S0272-6386(99)70432-4}}</ref><ref name=":3">{{Cite journal|last=Ra|first=Kyle|last2=Ma|first2=Gertz|date=1995|title=Primary systemic amyloidosis: clinical and laboratory features in 474 cases|url=https://pubmed.ncbi.nlm.nih.gov/7878478/|language=en|pmid=7878478}}</ref><ref>{{Cite journal|last=Preud'homme|first=Jean-Louis|last2=Aucouturier|first2=Pierre|last3=Touchard|first3=Guy|last4=Striker|first4=Liliane|last5=Khamlichi|first5=Ahmed Amine|last6=Rocca|first6=Anna|last7=Denoroy|first7=Luc|last8=Cogné|first8=Michel|date=1994|title=Monoclonal immunoglobulin deposition disease (Randall type). Relationship with structural abnormalities of immunoglobulin chains|url=https://linkinghub.elsevier.com/retrieve/pii/S0085253815586365|journal=Kidney International|language=en|volume=46|issue=4|pages=965–972|doi=10.1038/ki.1994.355}}</ref><ref>{{Cite journal|last=Preud'Homme|first=Jean-Louis|last2=Aucouturier|first2=Pierre|last3=Touchard|first3=Guy|last4=Khamlichi|first4=Amhed Amine|last5=Rocca|first5=Anna|last6=Denoroy|first6=Luc|last7=Cogne|first7=Michel|date=1994|title=Monoclonal immunoglobulin deposition disease: A review of immunoglobulin chain alterations|url=https://linkinghub.elsevier.com/retrieve/pii/0192056194900329|journal=International Journal of Immunopharmacology|language=en|volume=16|issue=5-6|pages=425–431|doi=10.1016/0192-0561(94)90032-9}}</ref><ref>{{Cite journal|last=Serpell|first=L. C.|last2=Sunde|first2=M.|last3=Blake|first3=C. C. F.|date=1997|title=The molecular basis of amyloidosis|url=http://link.springer.com/10.1007/s000180050107|journal=Cellular and Molecular Life Sciences|volume=53|issue=12|pages=871|doi=10.1007/s000180050107}}</ref><ref name=":0">McKenna RW, et al., (2017). Plasma cell neoplasms: Monoclonal immunoglobulin deposition diseases, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow, SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p254-255. </ref>
*These monoclonal Ig deposition diseases overlap as clinically similar conditions—but likely represent chemically distinctive manifestations of similar pathological processes, which can be placed into two major categories: 1) primary amyloidosis (detailed herein); 2) [[Light Chain and Heavy Chain Deposition Disease|light chain and heavy chain deposition diseases]]<ref name=":0" /><ref name=":1">{{Cite journal|last=Ra|first=Kyle|last2=A|first2=Linos|last3=Cm|first3=Beard|last4=Rp|first4=Linke|last5=Ma|first5=Gertz|last6=Wm|first6=O'Fallon|last7=Lt|first7=Kurland|date=1992|title=Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989|url=https://pubmed.ncbi.nlm.nih.gov/1558973/|language=en|pmid=1558973}}</ref>
*An acquired systemic amyloidosis, primary amyloidosis or the preferred term “AL amyloidosis,” results from a plasma cell (pc) or in rare instances, a lymphoplasmacytic neoplasm
*AL amyloidosis is a rare clonal plasma cell dyscrasia, with a particularly devastating clinical phenotype that results from the extracellular amyloid fibril deposition in vital organs<ref name=":14">{{Cite journal|last=Ah|first=Bryce|last2=Rp|first2=Ketterling|last3=Ma|first3=Gertz|last4=M|first4=Lacy|last5=Ra|first5=Knudson|last6=S|first6=Zeldenrust|last7=S|first7=Kumar|last8=S|first8=Hayman|last9=F|first9=Buadi|date=2009|title=Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/19211640/|language=en|doi=10.3324/haematol.13369|pmc=PMC2649355|pmid=19211640}}</ref><ref name=":4">{{Cite journal|last=G|first=Merlini|date=2017|title=AL amyloidosis: from molecular mechanisms to targeted therapies|url=https://pubmed.ncbi.nlm.nih.gov/29222231/|language=en|doi=10.1182/asheducation-2017.1.1|pmc=PMC6142527|pmid=29222231}}</ref><ref>{{Cite journal|last=Ryšavá|first=Romana|date=2019|title=AL amyloidosis: advances in diagnostics and treatment|url=https://academic.oup.com/ndt/article/34/9/1460/5123556|journal=Nephrology Dialysis Transplantation|language=en|volume=34|issue=9|pages=1460–1466|doi=10.1093/ndt/gfy291|issn=0931-0509}}</ref>
*The AL amyloid fibrils derive from ''N-''terminal region of monoclonal immunoglobulin light chains that consist of the whole or part of the variable (V<sub>I</sub>) domain<ref name=":2">{{Cite journal|date=2004|title=Guidelines on the diagnosis and management of AL amyloidosis|url=http://doi.wiley.com/10.1111/j.1365-2141.2004.04970.x|journal=British Journal of Haematology|language=en|volume=125|issue=6|pages=681–700|doi=10.1111/j.1365-2141.2004.04970.x|issn=0007-1048}}</ref>
**The structure and unique nature of all monoclonal light chains influences their inherent propensity (for some) to form amyloid fibrils<ref name=":2" />
**The amyloid formed from monoclonal light chains can exist in a partly unfolded state, which involves loss of tertiary or higher order structures<ref name=":2" />. Amyloids will readily aggregate in the ß-sheet structure to create protofilaments and fibril; this process is progressive as a ‘seeding” event serves as a template that facilities further amyloid deposition, which allows expansion of deposition by capturing further precursor molecules<ref name=":2" />
==Synonyms / Terminology==
*Immunoglobulin light chain amyloidosis (AL)
*AL amyloidosis (preferred in recent literature over Primary Amyloidosis, the WHO term)
*AL amyloidosis (ALA)
==Epidemiology / Prevalence==
*AL amyloidosis is an uncommon disorder and its exact incidence is unknown<ref name=":8">{{Cite journal|last=Gertz|first=Morie A.|date=2018|title=Immunoglobulin light chain amyloidosis: 2018 Update on diagnosis, prognosis, and treatment: GERTZ|url=http://doi.wiley.com/10.1002/ajh.25149|journal=American Journal of Hematology|language=en|volume=93|issue=9|pages=1169–1180|doi=10.1002/ajh.25149}}</ref>
*Within the US, the incidence is estimated at 9-14 cases per million person years, but the true prevalence may be higher due to under diagnosis<ref name=":1" /><ref name=":5">{{Cite journal|last=Staron|first=Andrew|last2=Connors|first2=Lawreen H.|last3=Ruberg|first3=Frederick L.|last4=Mendelson|first4=Lisa M.|last5=Sanchorawala|first5=Vaishali|date=2019|title=A new era of amyloidosis: the trends at a major US referral centre|url=https://www.tandfonline.com/doi/full/10.1080/13506129.2019.1640672|journal=Amyloid|language=en|volume=26|issue=4|pages=192–196|doi=10.1080/13506129.2019.1640672|issn=1350-6129}}</ref><ref name=":6">{{Cite journal|last=Vaxman|first=Iuliana|last2=Gertz|first2=Morie|date=2020|title=When to Suspect a Diagnosis of Amyloidosis|url=https://www.karger.com/Article/FullText/506617|journal=Acta Haematologica|language=en|pages=1–8|doi=10.1159/000506617|issn=0001-5792}}</ref>
*Considered a disease of the elderly, the incidence of AL amyloidosis increases with age<ref name=":1" /><ref name=":5" />
**A small proportion of patients (~1.3%) are diagnosed under the age of 34, with the median age at diagnosis of 63 years of age<ref name=":7">{{Cite journal|last=Tp|first=Quock|last2=T|first2=Yan|last3=E|first3=Chang|last4=S|first4=Guthrie|last5=Ms|first5=Broder|date=2018|title=Epidemiology of AL amyloidosis: a real-world study using US claims data|url=https://pubmed.ncbi.nlm.nih.gov/29748430/|language=en|doi=10.1182/bloodadvances.2018016402|pmc=PMC5965052|pmid=29748430}}</ref>
*There is a male predominance, with men reported in recent studies to account for 55-70% of patients<ref name=":3" /><ref name=":7" /><ref name=":15">{{Cite journal|last=Ra|first=Kyle|last2=Pr|first2=Greipp|last3=Wm|first3=O'Fallon|date=1986|title=Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases|url=https://pubmed.ncbi.nlm.nih.gov/3719098/|language=en|pmid=3719098}}</ref>
*There is limited data regarding AL amyloidosis incidence across ethnic populations, however, the disease is known to occur in all races and geographical regions<ref name=":0" />
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
EXAMPLE B-symptoms (weight loss, fever, night sweats)
EXAMPLE Fatigue
EXAMPLE Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|EXAMPLE Cytopenias
EXAMPLE Lymphocytosis (low level)
|}
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
*The signs and symptoms that raise the clinical suspicion for a possible diagnosis of amyloidosis are generally nonspecific; therefore, the establishment of an AL amyloidosis is difficult and is highly reliant upon a clinical suspicion<ref name=":6" />
*Clinical presentations vary, ranging from more rapidly progressive symptoms to slowly evolving or a paucity of symptoms among others<ref name=":5" />
*Nearly 25% of patients are diagnosed late, and many present with advanced, irreversible cardiac damage, and often succumb to within 12 months of the diagnosis<ref name=":4" />
*Clinical presentations generally relate and are of a consequence of amyloid in organs and tissues, and it is often the presentation of symptoms within a particular organ that predominate, which initiates the diagnosis<ref name=":4" /><ref name=":6" />
*Signs of the disease in the early stages include peripheral neuropathy (~15-20%), carpal tunnel syndrome (~21%), and bone pain (~5%)<ref name=":0" />. Other major symptoms, in addition to the extremely common presenting symptoms of fatigue and weight loss, relate to congestive heart failure (~15-20%), nephrotic syndrome (~28%), or malabsorption (~5%) are common<ref name=":3" /><ref name=":0" />
*Physical observations include hepatomegaly (~25-30%), macroglossia (~10%), and purpura, commonly of periorbital or facial presentation (~15%)<ref name=":3" />
*Individuals with congestive heart failure or nephrotic syndrome often present with edema<ref name=":3" />
*Few patients present with splenomegaly, lymphadenopathy, skin and soft tissue thickening, a hoarse voice (due to vocal cord infiltration), hypoadrenalism or hypothyroidism (due to deposits within the adrenal or thyroid glands, respectively)<ref name=":16">{{Cite journal|last=Mahmood|first=S.|last2=Palladini|first2=G.|last3=Sanchorawala|first3=V.|last4=Wechalekar|first4=A.|date=2014|title=Update on treatment of light chain amyloidosis|url=http://www.haematologica.org/cgi/doi/10.3324/haematol.2013.087619|journal=Haematologica|language=en|volume=99|issue=2|pages=209–221|doi=10.3324/haematol.2013.087619|issn=0390-6078|pmc=PMC3912950|pmid=24497558}}</ref>
*Overlooking the diagnosis of AL amyloidosis leads to therapy delay, and is a relatively common event, and it represents an error of diagnostic consideration which has resulted in an unsatisfactory survival for patients<ref name=":8" />
</blockquote>
==Sites of Involvement==
*The accumulation of amyloid light chain progressively disrupts numerous tissues and organs, e.g. subcutaneous fat, kidneys, heart, liver, gastrointestinal tracts, peripheral nervous system, and bone marrow, ultimately leading to organ failure<ref name=":0" />
*The deposition of amyloid does not evoke (or of little) reaction locally within the tissues, and there is poor correlation between the level of amyloid depositions and the degree of impairment to organ function<ref name=":2" />
*The morbidity and mortality in AL amyloidosis results from the effects of the toxic monoclonal protein, and impact to cardiac function is a critical determinate of survival<ref>{{Cite journal|last=Comenzo|first=R L|last2=Reece|first2=D|last3=Palladini|first3=G|last4=Seldin|first4=D|last5=Sanchorawala|first5=V|last6=Landau|first6=H|last7=Falk|first7=R|last8=Wells|first8=K|last9=Solomon|first9=A|date=2012|title=Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis|url=http://www.nature.com/articles/leu2012100|journal=Leukemia|language=en|volume=26|issue=11|pages=2317–2325|doi=10.1038/leu.2012.100|issn=0887-6924}}</ref><ref>{{Cite journal|last=Kumar|first=Shaji|last2=Dispenzieri|first2=Angela|last3=Lacy|first3=Martha Q.|last4=Hayman|first4=Suzanne R.|last5=Buadi|first5=Francis K.|last6=Colby|first6=Colin|last7=Laumann|first7=Kristina|last8=Zeldenrust|first8=Steve R.|last9=Leung|first9=Nelson|date=2012|title=Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements|url=http://ascopubs.org/doi/10.1200/JCO.2011.38.5724|journal=Journal of Clinical Oncology|language=en|volume=30|issue=9|pages=989–995|doi=10.1200/JCO.2011.38.5724|issn=0732-183X|pmc=PMC3675680|pmid=22331953}}</ref>
*AL amyloidosis is a progressive and fatal disease, with significant mortality within one year of diagnosis<ref name=":4" /><ref name=":17">{{Cite journal|last=Ra|first=Kyle|last2=Ma|first2=Gertz|last3=Pr|first3=Greipp|last4=Te|first4=Witzig|last5=Ja|first5=Lust|last6=Mq|first6=Lacy|last7=Tm|first7=Therneau|date=1999|title=Long-term survival (10 years or more) in 30 patients with primary amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/9920856/|language=en|pmid=9920856}}</ref>
==Morphologic Features==
Put your text here
==Immunophenotype==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||EXAMPLE CD1
|-
|Positive (subset)||EXAMPLE CD2
|-
|Negative (universal)||EXAMPLE CD3
|-
|Negative (subset)||EXAMPLE CD4
|}
==Chromosomal Rearrangements (Gene Fusions)==
Put your text here and fill in the table
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference)
|Yes
|No
|Yes
|EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
|}
<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}
Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and [[Multiple Myeloma]] (MM). However, notably, the frequency of the [t(11;14)(q13;q32), ''IGH-CCND1''] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and [[Multiple Myeloma|MM]]. The [t(11;14)(q13;q32), ''IGH-CCND1''] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and [[Multiple Myeloma|MM]] (15-20%)<ref name=":0" /><ref name=":9" />. The [t(11;14)(q13;q32), ''IGH-CCND1''] fusion results from the juxtaposition of the ''CCND1'' proto-oncogene at 11q13 with the immunoglobulin heavy chain (''IGH'') locus at 14q32<ref>{{Cite journal|last=Hayman|first=Suzanne R.|last2=Bailey|first2=Richard J.|last3=Jalal|first3=Syed M.|last4=Ahmann|first4=Gregory J.|last5=Dispenzieri|first5=Angela|last6=Gertz|first6=Morie A.|last7=Greipp|first7=Philip R.|last8=Kyle|first8=Robert A.|last9=Lacy|first9=Martha Q.|date=2001|title=Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis|url=https://ashpublications.org/blood/article/98/7/2266/107138/Translocations-involving-the-immunoglobulin|journal=Blood|language=en|volume=98|issue=7|pages=2266–2268|doi=10.1182/blood.V98.7.2266|issn=1528-0020}}</ref><ref>{{Cite journal|last=Fonseca|first=Rafael|last2=Rajkumar|first2=S. Vincent|last3=Ahmann|first3=Gregory J.|last4=Jalal|first4=Syed M.|last5=Hoyer|first5=James D.|last6=Gertz|first6=Morie A.|last7=Kyle|first7=Robert A.|last8=Greipp|first8=Philip R.|last9=Dewald|first9=Gordon W.|date=2000|title=FISH Demonstrates Treatment-Related Chromosome Damage in Myeloid but not Plasma Cells in Primary Systemic Amyloidosis|url=http://www.tandfonline.com/doi/full/10.3109/10428190009065839|journal=Leukemia & Lymphoma|language=en|volume=39|issue=3-4|pages=391–395|doi=10.3109/10428190009065839|issn=1042-8194}}</ref><ref>{{Cite journal|last=Saleem|first=Mohamed|last2=Yusoff|first2=Narazah Mohd|date=2016|title=Fusion genes in malignant neoplastic disorders of haematopoietic system|url=https://www.tandfonline.com/doi/full/10.1080/10245332.2015.1106816|journal=Hematology|language=en|volume=21|issue=9|pages=501–512|doi=10.1080/10245332.2015.1106816|issn=1607-8454}}</ref>.
</blockquote>
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
An early stage diagnosis provides patients with the broadest options for treatment, including eligibility for dose intensive chemotherapy regiments. However, the diagnosis requires a high clinical suspicion in individuals with nephrotic range proteinuria with or without renal insufficiency, non-dilated cardiomyopathy, peripheral neuropathy, hepatomegaly or automatic neuropathy in the presence (or absence) of paraprotein detectable in the serum or urine<ref name=":2" />. Prognosis is highly variable, however, it is extremely poor in the absence of treatment. Nearly twenty years ago, the median survival was dismal at 1-2 years, with less than 5% of all AL amyloidosis patients alive ten or more years following diagnosis, however within the last decade this median survival has changed dramatically, and ~30-40% patients survive more than ten years<ref name=":3" /><ref name=":4" /><ref name=":17" />. The most frequent cause of death (reported in ~40% of cases) is the presence of amyloid-related cardiac disease<ref name=":15" /><ref>{{Cite journal|last=Warsame|first=R|last2=Kumar|first2=S K|last3=Gertz|first3=M A|last4=Lacy|first4=M Q|last5=Buadi|first5=F K|last6=Hayman|first6=S R|last7=Leung|first7=N|last8=Dingli|first8=D|last9=Lust|first9=J A|date=2015|title=Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death|url=http://www.nature.com/articles/bcj201534|journal=Blood Cancer Journal|language=en|volume=5|issue=5|pages=e310–e310|doi=10.1038/bcj.2015.34|issn=2044-5385|pmc=PMC4423220|pmid=25933374}}</ref><ref>{{Cite journal|last=Tahir|first=Usman A.|last2=Doros|first2=Gheorghe|last3=Kim|first3=John S.|last4=Connors|first4=Lawreen H.|last5=Seldin|first5=David C.|last6=Sam|first6=Flora|date=2019|title=Predictors of Mortality in Light Chain Cardiac Amyloidosis with Heart Failure|url=http://www.nature.com/articles/s41598-019-44912-x|journal=Scientific Reports|language=en|volume=9|issue=1|doi=10.1038/s41598-019-44912-x|issn=2045-2322|pmc=PMC6561903|pmid=31189919}}</ref>.
To preserve and improve the function of organs infiltrated by amyloid deposits, treatments focus on substantially reducing the supply of monoclonal immunoglobulin light chains to stabilize or regress existing amyloid deposits<ref name=":16" /><ref>{{Cite journal|last=Jd|first=Gillmore|last2=Pn|first2=Hawkins|last3=Mb|first3=Pepys|date=1997|title=Amyloidosis: a review of recent diagnostic and therapeutic developments|url=https://pubmed.ncbi.nlm.nih.gov/9375734/|language=en|pmid=9375734}}</ref>. Chemotherapies used are based on regimens proven effective in patients with multiple myeloma, however clinical benefits are often delayed for many months to allow for adequate suppression of an underlying plasma cell dyscrasia<ref name=":2" />. These range from low, intermediate, or high dose approaches alone or in combination with other newly emerging novel therapies<ref name=":2" /><ref>National Comprehensive Cancer Network. Systemic Light Chain Amyloidosis (Version 1.2020). <nowiki>https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf</nowiki> Accessed July 20th, 2020.</ref>. More intensive chemotherapies are associated with intense treatment related toxicity. Recent studies have linked the presence of specific genetic profiles (i.e. t(11;14)) to poor outcomes and suggested that the use of specific therapies (i.e. bortezomib) are associated with the poorest of outcomes, however, this link has not been firmly established—inversely patients with 1q deletion have superior outcomes when treated on bortezomib-based regimens<ref name=":14" /><ref name=":4" /><ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Kunz|first3=Christina|last4=Granzow|first4=Martin|last5=Benner|first5=Axel|last6=Seckinger|first6=Anja|last7=Kimmich|first7=Christoph|last8=Goldschmidt|first8=Hartmut|last9=Ho|first9=Anthony D.|date=2015|title=Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With Bortezomib-Based Regimens|url=http://ascopubs.org/doi/10.1200/JCO.2014.57.4947|journal=Journal of Clinical Oncology|language=en|volume=33|issue=12|pages=1371–1378|doi=10.1200/JCO.2014.57.4947|issn=0732-183X}}</ref>.
</blockquote>
==Individual Region Genomic Gain/Loss/LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>
{| class="wikitable sortable"
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE
7
|EXAMPLE Loss
|EXAMPLE
chr7:1- 159,335,973 [hg38]
|EXAMPLE
chr7
|Yes
|Yes
|No
|EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
|-
|EXAMPLE
8
|EXAMPLE Gain
|EXAMPLE
chr8:1-145,138,636 [hg38]
|EXAMPLE
chr8
|No
|No
|No
|EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference).
|}
<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see [[Characteristic chromosomal aberrations /Patterns]])<ref name=":12" />. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in [[Multiple Myeloma|MM]]; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q<ref name=":13">{{Cite journal|last=Paiva|first=Bruno|last2=Martinez-Lopez|first2=Joaquin|last3=Corchete|first3=Luis A.|last4=Sanchez-Vega|first4=Beatriz|last5=Rapado|first5=Inmaculada|last6=Puig|first6=Noemi|last7=Barrio|first7=Santiago|last8=Sanchez|first8=Maria-Luz|last9=Alignani|first9=Diego|date=2016|title=Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis|url=https://ashpublications.org/blood/article/127/24/3035/35439/Phenotypic-transcriptomic-and-genomic-features-of|journal=Blood|language=en|volume=127|issue=24|pages=3035–3039|doi=10.1182/blood-2015-10-673095|issn=0006-4971}}</ref>. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)<ref name=":12" />. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort<ref name=":12" />. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(''v'';14) ''IGH-''unknown partner<ref name=":12" /><ref>{{Cite journal|last=Cremer|first=Friedrich W.|last2=Bila|first2=Jelena|last3=Buck|first3=Isabelle|last4=Kartal|first4=Mutlu|last5=Hose|first5=Dirk|last6=Ittrich|first6=Carina|last7=Benner|first7=Axel|last8=Raab|first8=Marc S.|last9=Theil|first9=Ann-Cathrin|date=2005|title=Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics|url=http://doi.wiley.com/10.1002/gcc.20231|journal=Genes, Chromosomes and Cancer|language=en|volume=44|issue=2|pages=194–203|doi=10.1002/gcc.20231|issn=1045-2257}}</ref>. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis<ref name=":13" />. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see [[Gene mutations (SNV/INVDEL)]]<ref name=":18">{{Cite journal|last=Huang|first=Xu-Fei|last2=Jian|first2=Sun|last3=Lu|first3=Jun-Liang|last4=Shen|first4=Kai-Ni|last5=Feng|first5=Jun|last6=Zhang|first6=Cong-Li|last7=Tian|first7=Zhuang|last8=Wang|first8=Jia-Li|last9=Lei|first9=Wan-Jun|date=2020|title=Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival|url=https://www.tandfonline.com/doi/full/10.1080/13506129.2019.1678464|journal=Amyloid|language=en|volume=27|issue=1|pages=36–44|doi=10.1080/13506129.2019.1678464|issn=1350-6129}}</ref>.
</blockquote>
==Characteristic Chromosomal Patterns==
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>
{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE
Co-deletion of 1p and 18q
|Yes
|No
|No
|EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}
Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations<ref name=":9">{{Cite journal|last=Bochtler|first=Tilmann|last2=Merz|first2=Maximilian|last3=Hielscher|first3=Thomas|last4=Granzow|first4=Martin|last5=Hoffmann|first5=Korbinian|last6=Krämer|first6=Alwin|last7=Raab|first7=Marc-Steffen|last8=Hillengass|first8=Jens|last9=Seckinger|first9=Anja|date=2018|title=Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma|url=https://ashpublications.org/bloodadvances/article/2/20/2607/16105/Cytogenetic-intraclonal-heterogeneity-of-plasma|journal=Blood Advances|language=en|volume=2|issue=20|pages=2607–2618|doi=10.1182/bloodadvances.2018023200|issn=2473-9529|pmc=PMC6199662|pmid=30327369}}</ref>. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence ''in situ'' Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases<ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Stölzel|first2=Friedrich|last3=Heilig|first3=Christoph E.|last4=Kunz|first4=Christina|last5=Mohr|first5=Brigitte|last6=Jauch|first6=Anna|last7=Janssen|first7=Johannes W.G.|last8=Kramer|first8=Michael|last9=Benner|first9=Axel|date=2013|title=Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia|url=http://ascopubs.org/doi/10.1200/JCO.2013.50.7921|journal=Journal of Clinical Oncology|language=en|volume=31|issue=31|pages=3898–3905|doi=10.1200/JCO.2013.50.7921|issn=0732-183X}}</ref><ref>{{Cite journal|last=Gw|first=Dewald|last2=Ra|first2=Kyle|last3=Ga|first3=Hicks|last4=Pr|first4=Greipp|date=1985|title=The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/3926026/|language=en|pmid=3926026}}</ref>. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with [[Multiple Myeloma|MM]] specific probe sets or panels. These panels vary, but may include enumeration of ''CKS1B'' (1q21), ''CDKN2C'' (1p32), D9Z1/D15Z4 (CEN9, CEN15), ''RB1'' (13q14), ''TP53'' (17p13), and break-apart probes for ''MYC'' (8q24.1) or ''IGH'' (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common ''IGH'' partners: [t(4;14)(p16.3;q32); ''IGH-FGFR3''], [t(6;14)(p21;q32); ''IGH-CCND3''], [t(11;14)(q13;q32); ''IGH-CCND1''], [t(14;16)(q32;q23); ''IGH-MAF''], [t(14;20)(q32;q12); ''IGH-MAFB'']. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), ''CCND1-IGH'' aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes<ref name=":10">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Cremer|first3=Friedrich W.|last4=Heiss|first4=Christiane|last5=Benner|first5=Axel|last6=Hose|first6=Dirk|last7=Moos|first7=Marion|last8=Bila|first8=Jelena|last9=Bartram|first9=Claus R.|date=2008|title=Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability|url=https://ashpublications.org/blood/article/111/9/4700/24510/Evaluation-of-the-cytogenetic-aberration-pattern|journal=Blood|language=en|volume=111|issue=9|pages=4700–4705|doi=10.1182/blood-2007-11-122101|issn=0006-4971}}</ref><ref name=":11">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Heiss|first3=Christiane|last4=Benner|first4=Axel|last5=Moos|first5=Marion|last6=Seckinger|first6=Anja|last7=Pschowski-Zuck|first7=Stephanie|last8=Kirn|first8=Désirée|last9=Neben|first9=Kai|date=2011|title=Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)|url=https://ashpublications.org/blood/article/117/14/3809/20514/Hyperdiploidy-is-less-frequent-in-AL-amyloidosis|journal=Blood|language=en|volume=117|issue=14|pages=3809–3815|doi=10.1182/blood-2010-02-268987|issn=0006-4971}}</ref><ref>{{Cite journal|last=Cj|first=Harrison|last2=H|first2=Mazzullo|last3=Fm|first3=Ross|last4=Kl|first4=Cheung|last5=G|first5=Gerrard|last6=L|first6=Harewood|last7=A|first7=Mehta|last8=Hj|first8=Lachmann|last9=Pn|first9=Hawkins|date=2002|title=Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/11972529/|language=en|pmid=11972529}}</ref><ref>{{Cite journal|last=Kobayashi|first=Hiroki|last2=Abe|first2=Yoshiaki|last3=Miura|first3=Daisuke|last4=Narita|first4=Kentaro|last5=Kitadate|first5=Akihiro|last6=Takeuchi|first6=Masami|last7=Matsue|first7=Kosei|date=2019|title=Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma|url=https://academic.oup.com/jjco/article/49/2/195/5272727|journal=Japanese Journal of Clinical Oncology|language=en|volume=49|issue=2|pages=195–198|doi=10.1093/jjco/hyy202|issn=1465-3621}}</ref>. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis<ref name=":10" /><ref name=":11" /><ref name=":12">{{Cite journal|last=Granzow|first=Martin|last2=Hegenbart|first2=Ute|last3=Hinderhofer|first3=Katrin|last4=Hose|first4=Dirk|last5=Seckinger|first5=Anja|last6=Bochtler|first6=Tilmann|last7=Hemminki|first7=Kari|last8=Goldschmidt|first8=Hartmut|last9=Schönland|first9=Stefan O.|date=2017|title=Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2016.160721|journal=Haematologica|language=en|volume=102|issue=7|pages=1281–1290|doi=10.3324/haematol.2016.160721|issn=0390-6078|pmc=PMC5566044|pmid=28341732}}</ref>. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(''v'';14) ''IGH-v'' translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and [[Multiple Myeloma|MM]] often carry gain of ''CKS1B'' (1q21), and deletions of 8p21 (''PNOC''), ''RB1'' (13q14), and ''TP53'' (17p13)<ref name=":9" />. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia<ref name=":9" />. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported<ref name=":4" /><ref>{{Cite journal|last=Muchtar|first=E|last2=Dispenzieri|first2=A|last3=Kumar|first3=S K|last4=Ketterling|first4=R P|last5=Dingli|first5=D|last6=Lacy|first6=M Q|last7=Buadi|first7=F K|last8=Hayman|first8=S R|last9=Kapoor|first9=P|date=2017|title=Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category|url=http://www.nature.com/articles/leu2016369|journal=Leukemia|language=en|volume=31|issue=7|pages=1562–1569|doi=10.1038/leu.2016.369|issn=0887-6924}}</ref>.
</blockquote>
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC / TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE: TP53; Variable LOF mutations
EXAMPLE:
EGFR; Exon 20 mutations
EXAMPLE: BRAF; Activating mutations
|EXAMPLE: TSG
|EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference)
|EXAMPLE: IDH1 R123H
|EXAMPLE: EGFR amplification
|
|
|
|EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
<br />
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
Few studies have evaluated the genetic profile of bone marrow plasma cells from AL amyloidosis patients<ref name=":12" /><ref>{{Cite journal|last=López-Corral|first=L|last2=Sarasquete|first2=M E|last3=Beà|first3=S|last4=García-Sanz|first4=R|last5=Mateos|first5=M V|last6=Corchete|first6=L A|last7=Sayagués|first7=J M|last8=García|first8=E M|last9=Bladé|first9=J|date=2012|title=SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status|url=http://www.nature.com/articles/leu2012128|journal=Leukemia|language=en|volume=26|issue=12|pages=2521–2529|doi=10.1038/leu.2012.128|issn=0887-6924}}</ref><ref name=":13" /><ref>{{Cite journal|last=Weinhold|first=N|last2=Försti|first2=A|last3=da Silva Filho|first3=M I|last4=Nickel|first4=J|last5=Campo|first5=C|last6=Hoffmann|first6=P|last7=Nöthen|first7=M M|last8=Hose|first8=D|last9=Goldschmidt|first9=H|date=2014|title=Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma|url=http://www.nature.com/articles/leu2014208|journal=Leukemia|language=en|volume=28|issue=11|pages=2254–2256|doi=10.1038/leu.2014.208|issn=0887-6924}}</ref>. A comprehensive evaluation by Paiva et al. (2016) identified 38 significantly deregulated (3 upregulated/35 downregulated) genes in AL amyloidosis plasma cells. Specifically, the tumor suppressor genes cadherin 1 (''CDH1'') and RCAN family member 3 (''RCAN''), and the pro-apoptotic genes GLI pathogenesis related 1 (''GLIPR1'') and Fas cell surface death receptor (''FAS'') were downregulated, whereas significant overexpression of the interferon induced transmembrane protein 1 (''IFITM1'') gene known to be associated with the development of aggressive solid tumors was observed<ref name=":13" /><ref>{{Cite journal|last=Yu|first=Fang|last2=Xie|first2=Dan|last3=Ng|first3=Samuel S.|last4=Lum|first4=Ching Tung|last5=Cai|first5=Mu-Yan|last6=Cheung|first6=William K.|last7=Kung|first7=Hsiang-Fu|last8=Lin|first8=Guimiao|last9=Wang|first9=Xiaomei|date=2015|title=IFITM1 promotes the metastasis of human colorectal cancer via CAV-1|url=https://linkinghub.elsevier.com/retrieve/pii/S0304383515005005|journal=Cancer Letters|language=en|volume=368|issue=1|pages=135–143|doi=10.1016/j.canlet.2015.07.034}}</ref>
Huang et al. (2019) identified four recurrent mutations in an AL amyloidosis cohort using a combination of WES and targeted gene sequencing panels<ref name=":18" />. The recurrent mutations include: ankyrin repeat and SOCS box containing 15 [''ASB15'' (c.844C>T)], activating signal cointegrator 1 complex subunit 3 [''ASCC3'' (c.1595A>G)], H1.4 linker histone, cluster member [''HIST1H1E'' (c.311C>T)] and KRAS proto-oncogene, GTPase [''KRAS'' (c.35G >A)]<ref name=":18" />. In addition, the presence of these mutations in the ''ASB15'', ''ASCC3'' and ''HIST1H1E'' genes were found to be associated with inferior overall survival<ref name=":18" />.
Overall, although AL amyloidosis and [[Multiple Myeloma|MM]] share similarity in recurrent genetic aberrations, the genetic profile of plasma cells in AL amyloidosis involves substantially fewer genetic alterations (that are largely unique from genes altered in [[Multiple Myeloma|MM]]) when compared to [[Multiple Myeloma|MM]]—where the deregulation of ~400 genes has been documented<ref name=":13" /><ref>{{Cite journal|last=Abraham|first=Roshini S.|last2=Ballman|first2=Karla V.|last3=Dispenzieri|first3=Angela|last4=Grill|first4=Diane E.|last5=Manske|first5=Michelle K.|last6=Price-Troska|first6=Tammy L.|last7=Paz|first7=Natalia Gonzalez|last8=Gertz|first8=Morie A.|last9=Fonseca|first9=Rafael|date=2005|title=Functional gene expression analysis of clonal plasma cells identifies a unique molecular profile for light chain amyloidosis|url=https://ashpublications.org/blood/article/105/2/794/20081/Functional-gene-expression-analysis-of-clonal|journal=Blood|language=en|volume=105|issue=2|pages=794–803|doi=10.1182/blood-2004-04-1424|issn=0006-4971}}</ref><ref>{{Cite journal|last=Davies|first=Faith E.|last2=Dring|first2=Ann M.|last3=Li|first3=Cheng|last4=Rawstron|first4=Andrew C.|last5=Shammas|first5=Masood A.|last6=O'Connor|first6=Sheila M.|last7=Fenton|first7=James A.L.|last8=Hideshima|first8=Teru|last9=Chauhan|first9=Dharminder|date=2003|title=Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis|url=https://ashpublications.org/blood/article/102/13/4504/17472/Insights-into-the-multistep-transformation-of-MGUS|journal=Blood|language=en|volume=102|issue=13|pages=4504–4511|doi=10.1182/blood-2003-01-0016|issn=0006-4971}}</ref>. Of note, individuals with t(11;14) had a lower total overall aberration burden when compared with other AL amyloidosis groups<ref name=":12" />.
===Other Mutations===
Genetic analysis may be used to distinguish AL amyloidosis from hereditary amyloidosis. Testing for mutations in the transthyretin, fibrinogen Aα‐chain, lysozyme or apolipoprotein A-I genes are associated with hereditary disease. Genetic testing is often necessary as clinical features between diseases may be indistinguishable and family history evaluations may not be reflective given reduced penetrance<ref>{{Cite journal|last=Lachmann|first=Helen J.|last2=Booth|first2=David R.|last3=Booth|first3=Susanne E.|last4=Bybee|first4=Alison|last5=Gilbertson|first5=Janet A.|last6=Gillmore|first6=Julian D.|last7=Pepys|first7=Mark B.|last8=Hawkins|first8=Philip N.|date=2002|title=Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis|url=http://www.nejm.org/doi/abs/10.1056/NEJMoa013354|journal=New England Journal of Medicine|language=en|volume=346|issue=23|pages=1786–1791|doi=10.1056/NEJMoa013354|issn=0028-4793}}</ref><ref>{{Cite journal|last=Li|first=Danyang|last2=Liu|first2=Dan|last3=Xu|first3=Hui|last4=Yu|first4=Xiao-juan|last5=Zhou|first5=Fu-de|last6=Zhao|first6=Ming-hui|last7=Wang|first7=Su-xia|date=2019|title=Typing of hereditary renal amyloidosis presenting with isolated glomerular amyloid deposition|url=https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-019-1667-5|journal=BMC Nephrology|language=en|volume=20|issue=1|doi=10.1186/s12882-019-1667-5|issn=1471-2369|pmc=PMC6929319|pmid=31870425}}</ref>.
</blockquote>
==Epigenomic Alterations==
Not applicable
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|EXAMPLE: MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|EXAMPLE: Unregulated cell division
|-
|EXAMPLE: KMT2C and ARID1A; Inactivating mutations
|EXAMPLE: Histone modification, chromatin remodeling
|EXAMPLE: Abnormal gene expression program
|}
==Genetic Diagnostic Testing Methods==
Put your text here
==Familial Forms==
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
==Additional Information==
Put your text here
==Links==
[[Monoclonal Immunoglobulin Deposition Diseases]]
Put your links here (use "Link" icon at top of page)
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
'''
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.
<nowiki>*</nowiki>''Citation of this Page'': “Immunoglobulin-related (AL) amyloidosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Immunoglobulin-related_(AL)_amyloidosis</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases I]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
{{Under Construction}}
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. The original page can be found at [[HAEM4:Primary Amyloidosis]].
}}</blockquote>
==Primary Author(s)*==
Heather E. Williams, PhD, MS, PgD, ErCLG
__TOC__
==Cancer Category/Type==
Mature B-cell neoplasms
==Cancer Sub-Classification / Subtype==
Monoclonal immunoglobulin deposition disease
==Definition / Description of Disease==
*A member of the group of “monoclonal immunoglobulin deposition diseases” that are characterized by visceral and soft tissue deposition of aberrant immunoglobulin (Ig), which subsequently results in organ dysfunction<ref>{{Cite journal|last=Aucouturier|first=Pierre|last2=Khamlichi|first2=Ahmed A.|last3=Touchard|first3=Guy|last4=Justrabo|first4=Eve|last5=Cogne|first5=Michel|last6=Chauffert|first6=Bruno|last7=Martin|first7=Francois|last8=Preud'homme|first8=Jean-Louis|date=1993|title=Heavy-Chain Deposition Disease|url=http://www.nejm.org/doi/abs/10.1056/NEJM199311043291905|journal=New England Journal of Medicine|language=en|volume=329|issue=19|pages=1389–1393|doi=10.1056/NEJM199311043291905|issn=0028-4793}}</ref><ref>{{Cite journal|last=J|first=Buxbaum|date=1992|title=Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease|url=https://pubmed.ncbi.nlm.nih.gov/1582976/|language=en|pmid=1582976}}</ref><ref>{{Cite journal|last=Herzenberg|first=Andrew M.|last2=Lien|first2=John|last3=Magil|first3=Alex B.|date=1996|title=Monoclonal heavy chain (immunoglobulin G3) deposition disease: report of a case|url=https://linkinghub.elsevier.com/retrieve/pii/S0272638696901419|journal=American Journal of Kidney Diseases|language=en|volume=28|issue=1|pages=128–131|doi=10.1016/S0272-6386(96)90141-9}}</ref><ref>{{Cite journal|last=Kambham|first=Neeraja|last2=Markowitz|first2=Glen S.|last3=Appel|first3=Gerald B.|last4=Kleiner|first4=Morton J.|last5=Aucouturier|first5=Pierre|last6=D'Agati|first6=Vivette D.|date=1999|title=Heavy chain deposition disease: The disease spectrum|url=https://linkinghub.elsevier.com/retrieve/pii/S0272638699704324|journal=American Journal of Kidney Diseases|language=en|volume=33|issue=5|pages=954–962|doi=10.1016/S0272-6386(99)70432-4}}</ref><ref name=":3">{{Cite journal|last=Ra|first=Kyle|last2=Ma|first2=Gertz|date=1995|title=Primary systemic amyloidosis: clinical and laboratory features in 474 cases|url=https://pubmed.ncbi.nlm.nih.gov/7878478/|language=en|pmid=7878478}}</ref><ref>{{Cite journal|last=Preud'homme|first=Jean-Louis|last2=Aucouturier|first2=Pierre|last3=Touchard|first3=Guy|last4=Striker|first4=Liliane|last5=Khamlichi|first5=Ahmed Amine|last6=Rocca|first6=Anna|last7=Denoroy|first7=Luc|last8=Cogné|first8=Michel|date=1994|title=Monoclonal immunoglobulin deposition disease (Randall type). Relationship with structural abnormalities of immunoglobulin chains|url=https://linkinghub.elsevier.com/retrieve/pii/S0085253815586365|journal=Kidney International|language=en|volume=46|issue=4|pages=965–972|doi=10.1038/ki.1994.355}}</ref><ref>{{Cite journal|last=Preud'Homme|first=Jean-Louis|last2=Aucouturier|first2=Pierre|last3=Touchard|first3=Guy|last4=Khamlichi|first4=Amhed Amine|last5=Rocca|first5=Anna|last6=Denoroy|first6=Luc|last7=Cogne|first7=Michel|date=1994|title=Monoclonal immunoglobulin deposition disease: A review of immunoglobulin chain alterations|url=https://linkinghub.elsevier.com/retrieve/pii/0192056194900329|journal=International Journal of Immunopharmacology|language=en|volume=16|issue=5-6|pages=425–431|doi=10.1016/0192-0561(94)90032-9}}</ref><ref>{{Cite journal|last=Serpell|first=L. C.|last2=Sunde|first2=M.|last3=Blake|first3=C. C. F.|date=1997|title=The molecular basis of amyloidosis|url=http://link.springer.com/10.1007/s000180050107|journal=Cellular and Molecular Life Sciences|volume=53|issue=12|pages=871|doi=10.1007/s000180050107}}</ref><ref name=":0">McKenna RW, et al., (2017). Plasma cell neoplasms: Monoclonal immunoglobulin deposition diseases, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow, SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p254-255. </ref>
*These monoclonal Ig deposition diseases overlap as clinically similar conditions—but likely represent chemically distinctive manifestations of similar pathological processes, which can be placed into two major categories: 1) primary amyloidosis (detailed herein); 2) [[Light Chain and Heavy Chain Deposition Disease|light chain and heavy chain deposition diseases]]<ref name=":0" /><ref name=":1">{{Cite journal|last=Ra|first=Kyle|last2=A|first2=Linos|last3=Cm|first3=Beard|last4=Rp|first4=Linke|last5=Ma|first5=Gertz|last6=Wm|first6=O'Fallon|last7=Lt|first7=Kurland|date=1992|title=Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989|url=https://pubmed.ncbi.nlm.nih.gov/1558973/|language=en|pmid=1558973}}</ref>
*An acquired systemic amyloidosis, primary amyloidosis or the preferred term “AL amyloidosis,” results from a plasma cell (pc) or in rare instances, a lymphoplasmacytic neoplasm
*AL amyloidosis is a rare clonal plasma cell dyscrasia, with a particularly devastating clinical phenotype that results from the extracellular amyloid fibril deposition in vital organs<ref name=":14">{{Cite journal|last=Ah|first=Bryce|last2=Rp|first2=Ketterling|last3=Ma|first3=Gertz|last4=M|first4=Lacy|last5=Ra|first5=Knudson|last6=S|first6=Zeldenrust|last7=S|first7=Kumar|last8=S|first8=Hayman|last9=F|first9=Buadi|date=2009|title=Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/19211640/|language=en|doi=10.3324/haematol.13369|pmc=PMC2649355|pmid=19211640}}</ref><ref name=":4">{{Cite journal|last=G|first=Merlini|date=2017|title=AL amyloidosis: from molecular mechanisms to targeted therapies|url=https://pubmed.ncbi.nlm.nih.gov/29222231/|language=en|doi=10.1182/asheducation-2017.1.1|pmc=PMC6142527|pmid=29222231}}</ref><ref>{{Cite journal|last=Ryšavá|first=Romana|date=2019|title=AL amyloidosis: advances in diagnostics and treatment|url=https://academic.oup.com/ndt/article/34/9/1460/5123556|journal=Nephrology Dialysis Transplantation|language=en|volume=34|issue=9|pages=1460–1466|doi=10.1093/ndt/gfy291|issn=0931-0509}}</ref>
*The AL amyloid fibrils derive from ''N-''terminal region of monoclonal immunoglobulin light chains that consist of the whole or part of the variable (V<sub>I</sub>) domain<ref name=":2">{{Cite journal|date=2004|title=Guidelines on the diagnosis and management of AL amyloidosis|url=http://doi.wiley.com/10.1111/j.1365-2141.2004.04970.x|journal=British Journal of Haematology|language=en|volume=125|issue=6|pages=681–700|doi=10.1111/j.1365-2141.2004.04970.x|issn=0007-1048}}</ref>
**The structure and unique nature of all monoclonal light chains influences their inherent propensity (for some) to form amyloid fibrils<ref name=":2" />
**The amyloid formed from monoclonal light chains can exist in a partly unfolded state, which involves loss of tertiary or higher order structures<ref name=":2" />. Amyloids will readily aggregate in the ß-sheet structure to create protofilaments and fibril; this process is progressive as a ‘seeding” event serves as a template that facilities further amyloid deposition, which allows expansion of deposition by capturing further precursor molecules<ref name=":2" />
==Synonyms / Terminology==
*Immunoglobulin light chain amyloidosis (AL)
*AL amyloidosis (preferred in recent literature over Primary Amyloidosis, the WHO term)
*AL amyloidosis (ALA)
==Epidemiology / Prevalence==
*AL amyloidosis is an uncommon disorder and its exact incidence is unknown<ref name=":8">{{Cite journal|last=Gertz|first=Morie A.|date=2018|title=Immunoglobulin light chain amyloidosis: 2018 Update on diagnosis, prognosis, and treatment: GERTZ|url=http://doi.wiley.com/10.1002/ajh.25149|journal=American Journal of Hematology|language=en|volume=93|issue=9|pages=1169–1180|doi=10.1002/ajh.25149}}</ref>
*Within the US, the incidence is estimated at 9-14 cases per million person years, but the true prevalence may be higher due to under diagnosis<ref name=":1" /><ref name=":5">{{Cite journal|last=Staron|first=Andrew|last2=Connors|first2=Lawreen H.|last3=Ruberg|first3=Frederick L.|last4=Mendelson|first4=Lisa M.|last5=Sanchorawala|first5=Vaishali|date=2019|title=A new era of amyloidosis: the trends at a major US referral centre|url=https://www.tandfonline.com/doi/full/10.1080/13506129.2019.1640672|journal=Amyloid|language=en|volume=26|issue=4|pages=192–196|doi=10.1080/13506129.2019.1640672|issn=1350-6129}}</ref><ref name=":6">{{Cite journal|last=Vaxman|first=Iuliana|last2=Gertz|first2=Morie|date=2020|title=When to Suspect a Diagnosis of Amyloidosis|url=https://www.karger.com/Article/FullText/506617|journal=Acta Haematologica|language=en|pages=1–8|doi=10.1159/000506617|issn=0001-5792}}</ref>
*Considered a disease of the elderly, the incidence of AL amyloidosis increases with age<ref name=":1" /><ref name=":5" />
**A small proportion of patients (~1.3%) are diagnosed under the age of 34, with the median age at diagnosis of 63 years of age<ref name=":7">{{Cite journal|last=Tp|first=Quock|last2=T|first2=Yan|last3=E|first3=Chang|last4=S|first4=Guthrie|last5=Ms|first5=Broder|date=2018|title=Epidemiology of AL amyloidosis: a real-world study using US claims data|url=https://pubmed.ncbi.nlm.nih.gov/29748430/|language=en|doi=10.1182/bloodadvances.2018016402|pmc=PMC5965052|pmid=29748430}}</ref>
*There is a male predominance, with men reported in recent studies to account for 55-70% of patients<ref name=":3" /><ref name=":7" /><ref name=":15">{{Cite journal|last=Ra|first=Kyle|last2=Pr|first2=Greipp|last3=Wm|first3=O'Fallon|date=1986|title=Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases|url=https://pubmed.ncbi.nlm.nih.gov/3719098/|language=en|pmid=3719098}}</ref>
*There is limited data regarding AL amyloidosis incidence across ethnic populations, however, the disease is known to occur in all races and geographical regions<ref name=":0" />
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
EXAMPLE B-symptoms (weight loss, fever, night sweats)
EXAMPLE Fatigue
EXAMPLE Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|EXAMPLE Cytopenias
EXAMPLE Lymphocytosis (low level)
|}
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
*The signs and symptoms that raise the clinical suspicion for a possible diagnosis of amyloidosis are generally nonspecific; therefore, the establishment of an AL amyloidosis is difficult and is highly reliant upon a clinical suspicion<ref name=":6" />
*Clinical presentations vary, ranging from more rapidly progressive symptoms to slowly evolving or a paucity of symptoms among others<ref name=":5" />
*Nearly 25% of patients are diagnosed late, and many present with advanced, irreversible cardiac damage, and often succumb to within 12 months of the diagnosis<ref name=":4" />
*Clinical presentations generally relate and are of a consequence of amyloid in organs and tissues, and it is often the presentation of symptoms within a particular organ that predominate, which initiates the diagnosis<ref name=":4" /><ref name=":6" />
*Signs of the disease in the early stages include peripheral neuropathy (~15-20%), carpal tunnel syndrome (~21%), and bone pain (~5%)<ref name=":0" />. Other major symptoms, in addition to the extremely common presenting symptoms of fatigue and weight loss, relate to congestive heart failure (~15-20%), nephrotic syndrome (~28%), or malabsorption (~5%) are common<ref name=":3" /><ref name=":0" />
*Physical observations include hepatomegaly (~25-30%), macroglossia (~10%), and purpura, commonly of periorbital or facial presentation (~15%)<ref name=":3" />
*Individuals with congestive heart failure or nephrotic syndrome often present with edema<ref name=":3" />
*Few patients present with splenomegaly, lymphadenopathy, skin and soft tissue thickening, a hoarse voice (due to vocal cord infiltration), hypoadrenalism or hypothyroidism (due to deposits within the adrenal or thyroid glands, respectively)<ref name=":16">{{Cite journal|last=Mahmood|first=S.|last2=Palladini|first2=G.|last3=Sanchorawala|first3=V.|last4=Wechalekar|first4=A.|date=2014|title=Update on treatment of light chain amyloidosis|url=http://www.haematologica.org/cgi/doi/10.3324/haematol.2013.087619|journal=Haematologica|language=en|volume=99|issue=2|pages=209–221|doi=10.3324/haematol.2013.087619|issn=0390-6078|pmc=PMC3912950|pmid=24497558}}</ref>
*Overlooking the diagnosis of AL amyloidosis leads to therapy delay, and is a relatively common event, and it represents an error of diagnostic consideration which has resulted in an unsatisfactory survival for patients<ref name=":8" />
</blockquote>
==Sites of Involvement==
*The accumulation of amyloid light chain progressively disrupts numerous tissues and organs, e.g. subcutaneous fat, kidneys, heart, liver, gastrointestinal tracts, peripheral nervous system, and bone marrow, ultimately leading to organ failure<ref name=":0" />
*The deposition of amyloid does not evoke (or of little) reaction locally within the tissues, and there is poor correlation between the level of amyloid depositions and the degree of impairment to organ function<ref name=":2" />
*The morbidity and mortality in AL amyloidosis results from the effects of the toxic monoclonal protein, and impact to cardiac function is a critical determinate of survival<ref>{{Cite journal|last=Comenzo|first=R L|last2=Reece|first2=D|last3=Palladini|first3=G|last4=Seldin|first4=D|last5=Sanchorawala|first5=V|last6=Landau|first6=H|last7=Falk|first7=R|last8=Wells|first8=K|last9=Solomon|first9=A|date=2012|title=Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis|url=http://www.nature.com/articles/leu2012100|journal=Leukemia|language=en|volume=26|issue=11|pages=2317–2325|doi=10.1038/leu.2012.100|issn=0887-6924}}</ref><ref>{{Cite journal|last=Kumar|first=Shaji|last2=Dispenzieri|first2=Angela|last3=Lacy|first3=Martha Q.|last4=Hayman|first4=Suzanne R.|last5=Buadi|first5=Francis K.|last6=Colby|first6=Colin|last7=Laumann|first7=Kristina|last8=Zeldenrust|first8=Steve R.|last9=Leung|first9=Nelson|date=2012|title=Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements|url=http://ascopubs.org/doi/10.1200/JCO.2011.38.5724|journal=Journal of Clinical Oncology|language=en|volume=30|issue=9|pages=989–995|doi=10.1200/JCO.2011.38.5724|issn=0732-183X|pmc=PMC3675680|pmid=22331953}}</ref>
*AL amyloidosis is a progressive and fatal disease, with significant mortality within one year of diagnosis<ref name=":4" /><ref name=":17">{{Cite journal|last=Ra|first=Kyle|last2=Ma|first2=Gertz|last3=Pr|first3=Greipp|last4=Te|first4=Witzig|last5=Ja|first5=Lust|last6=Mq|first6=Lacy|last7=Tm|first7=Therneau|date=1999|title=Long-term survival (10 years or more) in 30 patients with primary amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/9920856/|language=en|pmid=9920856}}</ref>
==Morphologic Features==
Put your text here
==Immunophenotype==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||EXAMPLE CD1
|-
|Positive (subset)||EXAMPLE CD2
|-
|Negative (universal)||EXAMPLE CD3
|-
|Negative (subset)||EXAMPLE CD4
|}
==Chromosomal Rearrangements (Gene Fusions)==
Put your text here and fill in the table
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference)
|Yes
|No
|Yes
|EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
|}
<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}
Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and [[Multiple Myeloma]] (MM). However, notably, the frequency of the [t(11;14)(q13;q32), ''IGH-CCND1''] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and [[Multiple Myeloma|MM]]. The [t(11;14)(q13;q32), ''IGH-CCND1''] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and [[Multiple Myeloma|MM]] (15-20%)<ref name=":0" /><ref name=":9" />. The [t(11;14)(q13;q32), ''IGH-CCND1''] fusion results from the juxtaposition of the ''CCND1'' proto-oncogene at 11q13 with the immunoglobulin heavy chain (''IGH'') locus at 14q32<ref>{{Cite journal|last=Hayman|first=Suzanne R.|last2=Bailey|first2=Richard J.|last3=Jalal|first3=Syed M.|last4=Ahmann|first4=Gregory J.|last5=Dispenzieri|first5=Angela|last6=Gertz|first6=Morie A.|last7=Greipp|first7=Philip R.|last8=Kyle|first8=Robert A.|last9=Lacy|first9=Martha Q.|date=2001|title=Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis|url=https://ashpublications.org/blood/article/98/7/2266/107138/Translocations-involving-the-immunoglobulin|journal=Blood|language=en|volume=98|issue=7|pages=2266–2268|doi=10.1182/blood.V98.7.2266|issn=1528-0020}}</ref><ref>{{Cite journal|last=Fonseca|first=Rafael|last2=Rajkumar|first2=S. Vincent|last3=Ahmann|first3=Gregory J.|last4=Jalal|first4=Syed M.|last5=Hoyer|first5=James D.|last6=Gertz|first6=Morie A.|last7=Kyle|first7=Robert A.|last8=Greipp|first8=Philip R.|last9=Dewald|first9=Gordon W.|date=2000|title=FISH Demonstrates Treatment-Related Chromosome Damage in Myeloid but not Plasma Cells in Primary Systemic Amyloidosis|url=http://www.tandfonline.com/doi/full/10.3109/10428190009065839|journal=Leukemia & Lymphoma|language=en|volume=39|issue=3-4|pages=391–395|doi=10.3109/10428190009065839|issn=1042-8194}}</ref><ref>{{Cite journal|last=Saleem|first=Mohamed|last2=Yusoff|first2=Narazah Mohd|date=2016|title=Fusion genes in malignant neoplastic disorders of haematopoietic system|url=https://www.tandfonline.com/doi/full/10.1080/10245332.2015.1106816|journal=Hematology|language=en|volume=21|issue=9|pages=501–512|doi=10.1080/10245332.2015.1106816|issn=1607-8454}}</ref>.
</blockquote>
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
An early stage diagnosis provides patients with the broadest options for treatment, including eligibility for dose intensive chemotherapy regiments. However, the diagnosis requires a high clinical suspicion in individuals with nephrotic range proteinuria with or without renal insufficiency, non-dilated cardiomyopathy, peripheral neuropathy, hepatomegaly or automatic neuropathy in the presence (or absence) of paraprotein detectable in the serum or urine<ref name=":2" />. Prognosis is highly variable, however, it is extremely poor in the absence of treatment. Nearly twenty years ago, the median survival was dismal at 1-2 years, with less than 5% of all AL amyloidosis patients alive ten or more years following diagnosis, however within the last decade this median survival has changed dramatically, and ~30-40% patients survive more than ten years<ref name=":3" /><ref name=":4" /><ref name=":17" />. The most frequent cause of death (reported in ~40% of cases) is the presence of amyloid-related cardiac disease<ref name=":15" /><ref>{{Cite journal|last=Warsame|first=R|last2=Kumar|first2=S K|last3=Gertz|first3=M A|last4=Lacy|first4=M Q|last5=Buadi|first5=F K|last6=Hayman|first6=S R|last7=Leung|first7=N|last8=Dingli|first8=D|last9=Lust|first9=J A|date=2015|title=Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death|url=http://www.nature.com/articles/bcj201534|journal=Blood Cancer Journal|language=en|volume=5|issue=5|pages=e310–e310|doi=10.1038/bcj.2015.34|issn=2044-5385|pmc=PMC4423220|pmid=25933374}}</ref><ref>{{Cite journal|last=Tahir|first=Usman A.|last2=Doros|first2=Gheorghe|last3=Kim|first3=John S.|last4=Connors|first4=Lawreen H.|last5=Seldin|first5=David C.|last6=Sam|first6=Flora|date=2019|title=Predictors of Mortality in Light Chain Cardiac Amyloidosis with Heart Failure|url=http://www.nature.com/articles/s41598-019-44912-x|journal=Scientific Reports|language=en|volume=9|issue=1|doi=10.1038/s41598-019-44912-x|issn=2045-2322|pmc=PMC6561903|pmid=31189919}}</ref>.
To preserve and improve the function of organs infiltrated by amyloid deposits, treatments focus on substantially reducing the supply of monoclonal immunoglobulin light chains to stabilize or regress existing amyloid deposits<ref name=":16" /><ref>{{Cite journal|last=Jd|first=Gillmore|last2=Pn|first2=Hawkins|last3=Mb|first3=Pepys|date=1997|title=Amyloidosis: a review of recent diagnostic and therapeutic developments|url=https://pubmed.ncbi.nlm.nih.gov/9375734/|language=en|pmid=9375734}}</ref>. Chemotherapies used are based on regimens proven effective in patients with multiple myeloma, however clinical benefits are often delayed for many months to allow for adequate suppression of an underlying plasma cell dyscrasia<ref name=":2" />. These range from low, intermediate, or high dose approaches alone or in combination with other newly emerging novel therapies<ref name=":2" /><ref>National Comprehensive Cancer Network. Systemic Light Chain Amyloidosis (Version 1.2020). <nowiki>https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf</nowiki> Accessed July 20th, 2020.</ref>. More intensive chemotherapies are associated with intense treatment related toxicity. Recent studies have linked the presence of specific genetic profiles (i.e. t(11;14)) to poor outcomes and suggested that the use of specific therapies (i.e. bortezomib) are associated with the poorest of outcomes, however, this link has not been firmly established—inversely patients with 1q deletion have superior outcomes when treated on bortezomib-based regimens<ref name=":14" /><ref name=":4" /><ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Kunz|first3=Christina|last4=Granzow|first4=Martin|last5=Benner|first5=Axel|last6=Seckinger|first6=Anja|last7=Kimmich|first7=Christoph|last8=Goldschmidt|first8=Hartmut|last9=Ho|first9=Anthony D.|date=2015|title=Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With Bortezomib-Based Regimens|url=http://ascopubs.org/doi/10.1200/JCO.2014.57.4947|journal=Journal of Clinical Oncology|language=en|volume=33|issue=12|pages=1371–1378|doi=10.1200/JCO.2014.57.4947|issn=0732-183X}}</ref>.
</blockquote>
==Individual Region Genomic Gain/Loss/LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>
{| class="wikitable sortable"
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE
7
|EXAMPLE Loss
|EXAMPLE
chr7:1- 159,335,973 [hg38]
|EXAMPLE
chr7
|Yes
|Yes
|No
|EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
|-
|EXAMPLE
8
|EXAMPLE Gain
|EXAMPLE
chr8:1-145,138,636 [hg38]
|EXAMPLE
chr8
|No
|No
|No
|EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference).
|}
<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see [[Characteristic chromosomal aberrations /Patterns]])<ref name=":12" />. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in [[Multiple Myeloma|MM]]; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q<ref name=":13">{{Cite journal|last=Paiva|first=Bruno|last2=Martinez-Lopez|first2=Joaquin|last3=Corchete|first3=Luis A.|last4=Sanchez-Vega|first4=Beatriz|last5=Rapado|first5=Inmaculada|last6=Puig|first6=Noemi|last7=Barrio|first7=Santiago|last8=Sanchez|first8=Maria-Luz|last9=Alignani|first9=Diego|date=2016|title=Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis|url=https://ashpublications.org/blood/article/127/24/3035/35439/Phenotypic-transcriptomic-and-genomic-features-of|journal=Blood|language=en|volume=127|issue=24|pages=3035–3039|doi=10.1182/blood-2015-10-673095|issn=0006-4971}}</ref>. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)<ref name=":12" />. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort<ref name=":12" />. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(''v'';14) ''IGH-''unknown partner<ref name=":12" /><ref>{{Cite journal|last=Cremer|first=Friedrich W.|last2=Bila|first2=Jelena|last3=Buck|first3=Isabelle|last4=Kartal|first4=Mutlu|last5=Hose|first5=Dirk|last6=Ittrich|first6=Carina|last7=Benner|first7=Axel|last8=Raab|first8=Marc S.|last9=Theil|first9=Ann-Cathrin|date=2005|title=Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics|url=http://doi.wiley.com/10.1002/gcc.20231|journal=Genes, Chromosomes and Cancer|language=en|volume=44|issue=2|pages=194–203|doi=10.1002/gcc.20231|issn=1045-2257}}</ref>. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis<ref name=":13" />. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see [[Gene mutations (SNV/INVDEL)]]<ref name=":18">{{Cite journal|last=Huang|first=Xu-Fei|last2=Jian|first2=Sun|last3=Lu|first3=Jun-Liang|last4=Shen|first4=Kai-Ni|last5=Feng|first5=Jun|last6=Zhang|first6=Cong-Li|last7=Tian|first7=Zhuang|last8=Wang|first8=Jia-Li|last9=Lei|first9=Wan-Jun|date=2020|title=Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival|url=https://www.tandfonline.com/doi/full/10.1080/13506129.2019.1678464|journal=Amyloid|language=en|volume=27|issue=1|pages=36–44|doi=10.1080/13506129.2019.1678464|issn=1350-6129}}</ref>.
</blockquote>
==Characteristic Chromosomal Patterns==
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>
{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE
Co-deletion of 1p and 18q
|Yes
|No
|No
|EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}
Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations<ref name=":9">{{Cite journal|last=Bochtler|first=Tilmann|last2=Merz|first2=Maximilian|last3=Hielscher|first3=Thomas|last4=Granzow|first4=Martin|last5=Hoffmann|first5=Korbinian|last6=Krämer|first6=Alwin|last7=Raab|first7=Marc-Steffen|last8=Hillengass|first8=Jens|last9=Seckinger|first9=Anja|date=2018|title=Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma|url=https://ashpublications.org/bloodadvances/article/2/20/2607/16105/Cytogenetic-intraclonal-heterogeneity-of-plasma|journal=Blood Advances|language=en|volume=2|issue=20|pages=2607–2618|doi=10.1182/bloodadvances.2018023200|issn=2473-9529|pmc=PMC6199662|pmid=30327369}}</ref>. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence ''in situ'' Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases<ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Stölzel|first2=Friedrich|last3=Heilig|first3=Christoph E.|last4=Kunz|first4=Christina|last5=Mohr|first5=Brigitte|last6=Jauch|first6=Anna|last7=Janssen|first7=Johannes W.G.|last8=Kramer|first8=Michael|last9=Benner|first9=Axel|date=2013|title=Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia|url=http://ascopubs.org/doi/10.1200/JCO.2013.50.7921|journal=Journal of Clinical Oncology|language=en|volume=31|issue=31|pages=3898–3905|doi=10.1200/JCO.2013.50.7921|issn=0732-183X}}</ref><ref>{{Cite journal|last=Gw|first=Dewald|last2=Ra|first2=Kyle|last3=Ga|first3=Hicks|last4=Pr|first4=Greipp|date=1985|title=The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/3926026/|language=en|pmid=3926026}}</ref>. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with [[Multiple Myeloma|MM]] specific probe sets or panels. These panels vary, but may include enumeration of ''CKS1B'' (1q21), ''CDKN2C'' (1p32), D9Z1/D15Z4 (CEN9, CEN15), ''RB1'' (13q14), ''TP53'' (17p13), and break-apart probes for ''MYC'' (8q24.1) or ''IGH'' (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common ''IGH'' partners: [t(4;14)(p16.3;q32); ''IGH-FGFR3''], [t(6;14)(p21;q32); ''IGH-CCND3''], [t(11;14)(q13;q32); ''IGH-CCND1''], [t(14;16)(q32;q23); ''IGH-MAF''], [t(14;20)(q32;q12); ''IGH-MAFB'']. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), ''CCND1-IGH'' aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes<ref name=":10">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Cremer|first3=Friedrich W.|last4=Heiss|first4=Christiane|last5=Benner|first5=Axel|last6=Hose|first6=Dirk|last7=Moos|first7=Marion|last8=Bila|first8=Jelena|last9=Bartram|first9=Claus R.|date=2008|title=Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability|url=https://ashpublications.org/blood/article/111/9/4700/24510/Evaluation-of-the-cytogenetic-aberration-pattern|journal=Blood|language=en|volume=111|issue=9|pages=4700–4705|doi=10.1182/blood-2007-11-122101|issn=0006-4971}}</ref><ref name=":11">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Heiss|first3=Christiane|last4=Benner|first4=Axel|last5=Moos|first5=Marion|last6=Seckinger|first6=Anja|last7=Pschowski-Zuck|first7=Stephanie|last8=Kirn|first8=Désirée|last9=Neben|first9=Kai|date=2011|title=Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)|url=https://ashpublications.org/blood/article/117/14/3809/20514/Hyperdiploidy-is-less-frequent-in-AL-amyloidosis|journal=Blood|language=en|volume=117|issue=14|pages=3809–3815|doi=10.1182/blood-2010-02-268987|issn=0006-4971}}</ref><ref>{{Cite journal|last=Cj|first=Harrison|last2=H|first2=Mazzullo|last3=Fm|first3=Ross|last4=Kl|first4=Cheung|last5=G|first5=Gerrard|last6=L|first6=Harewood|last7=A|first7=Mehta|last8=Hj|first8=Lachmann|last9=Pn|first9=Hawkins|date=2002|title=Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/11972529/|language=en|pmid=11972529}}</ref><ref>{{Cite journal|last=Kobayashi|first=Hiroki|last2=Abe|first2=Yoshiaki|last3=Miura|first3=Daisuke|last4=Narita|first4=Kentaro|last5=Kitadate|first5=Akihiro|last6=Takeuchi|first6=Masami|last7=Matsue|first7=Kosei|date=2019|title=Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma|url=https://academic.oup.com/jjco/article/49/2/195/5272727|journal=Japanese Journal of Clinical Oncology|language=en|volume=49|issue=2|pages=195–198|doi=10.1093/jjco/hyy202|issn=1465-3621}}</ref>. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis<ref name=":10" /><ref name=":11" /><ref name=":12">{{Cite journal|last=Granzow|first=Martin|last2=Hegenbart|first2=Ute|last3=Hinderhofer|first3=Katrin|last4=Hose|first4=Dirk|last5=Seckinger|first5=Anja|last6=Bochtler|first6=Tilmann|last7=Hemminki|first7=Kari|last8=Goldschmidt|first8=Hartmut|last9=Schönland|first9=Stefan O.|date=2017|title=Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2016.160721|journal=Haematologica|language=en|volume=102|issue=7|pages=1281–1290|doi=10.3324/haematol.2016.160721|issn=0390-6078|pmc=PMC5566044|pmid=28341732}}</ref>. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(''v'';14) ''IGH-v'' translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and [[Multiple Myeloma|MM]] often carry gain of ''CKS1B'' (1q21), and deletions of 8p21 (''PNOC''), ''RB1'' (13q14), and ''TP53'' (17p13)<ref name=":9" />. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia<ref name=":9" />. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported<ref name=":4" /><ref>{{Cite journal|last=Muchtar|first=E|last2=Dispenzieri|first2=A|last3=Kumar|first3=S K|last4=Ketterling|first4=R P|last5=Dingli|first5=D|last6=Lacy|first6=M Q|last7=Buadi|first7=F K|last8=Hayman|first8=S R|last9=Kapoor|first9=P|date=2017|title=Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category|url=http://www.nature.com/articles/leu2016369|journal=Leukemia|language=en|volume=31|issue=7|pages=1562–1569|doi=10.1038/leu.2016.369|issn=0887-6924}}</ref>.
</blockquote>
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC / TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE: TP53; Variable LOF mutations
EXAMPLE:
EGFR; Exon 20 mutations
EXAMPLE: BRAF; Activating mutations
|EXAMPLE: TSG
|EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference)
|EXAMPLE: IDH1 R123H
|EXAMPLE: EGFR amplification
|
|
|
|EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
<br />
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
Few studies have evaluated the genetic profile of bone marrow plasma cells from AL amyloidosis patients<ref name=":12" /><ref>{{Cite journal|last=López-Corral|first=L|last2=Sarasquete|first2=M E|last3=Beà|first3=S|last4=García-Sanz|first4=R|last5=Mateos|first5=M V|last6=Corchete|first6=L A|last7=Sayagués|first7=J M|last8=García|first8=E M|last9=Bladé|first9=J|date=2012|title=SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status|url=http://www.nature.com/articles/leu2012128|journal=Leukemia|language=en|volume=26|issue=12|pages=2521–2529|doi=10.1038/leu.2012.128|issn=0887-6924}}</ref><ref name=":13" /><ref>{{Cite journal|last=Weinhold|first=N|last2=Försti|first2=A|last3=da Silva Filho|first3=M I|last4=Nickel|first4=J|last5=Campo|first5=C|last6=Hoffmann|first6=P|last7=Nöthen|first7=M M|last8=Hose|first8=D|last9=Goldschmidt|first9=H|date=2014|title=Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma|url=http://www.nature.com/articles/leu2014208|journal=Leukemia|language=en|volume=28|issue=11|pages=2254–2256|doi=10.1038/leu.2014.208|issn=0887-6924}}</ref>. A comprehensive evaluation by Paiva et al. (2016) identified 38 significantly deregulated (3 upregulated/35 downregulated) genes in AL amyloidosis plasma cells. Specifically, the tumor suppressor genes cadherin 1 (''CDH1'') and RCAN family member 3 (''RCAN''), and the pro-apoptotic genes GLI pathogenesis related 1 (''GLIPR1'') and Fas cell surface death receptor (''FAS'') were downregulated, whereas significant overexpression of the interferon induced transmembrane protein 1 (''IFITM1'') gene known to be associated with the development of aggressive solid tumors was observed<ref name=":13" /><ref>{{Cite journal|last=Yu|first=Fang|last2=Xie|first2=Dan|last3=Ng|first3=Samuel S.|last4=Lum|first4=Ching Tung|last5=Cai|first5=Mu-Yan|last6=Cheung|first6=William K.|last7=Kung|first7=Hsiang-Fu|last8=Lin|first8=Guimiao|last9=Wang|first9=Xiaomei|date=2015|title=IFITM1 promotes the metastasis of human colorectal cancer via CAV-1|url=https://linkinghub.elsevier.com/retrieve/pii/S0304383515005005|journal=Cancer Letters|language=en|volume=368|issue=1|pages=135–143|doi=10.1016/j.canlet.2015.07.034}}</ref>
Huang et al. (2019) identified four recurrent mutations in an AL amyloidosis cohort using a combination of WES and targeted gene sequencing panels<ref name=":18" />. The recurrent mutations include: ankyrin repeat and SOCS box containing 15 [''ASB15'' (c.844C>T)], activating signal cointegrator 1 complex subunit 3 [''ASCC3'' (c.1595A>G)], H1.4 linker histone, cluster member [''HIST1H1E'' (c.311C>T)] and KRAS proto-oncogene, GTPase [''KRAS'' (c.35G >A)]<ref name=":18" />. In addition, the presence of these mutations in the ''ASB15'', ''ASCC3'' and ''HIST1H1E'' genes were found to be associated with inferior overall survival<ref name=":18" />.
Overall, although AL amyloidosis and [[Multiple Myeloma|MM]] share similarity in recurrent genetic aberrations, the genetic profile of plasma cells in AL amyloidosis involves substantially fewer genetic alterations (that are largely unique from genes altered in [[Multiple Myeloma|MM]]) when compared to [[Multiple Myeloma|MM]]—where the deregulation of ~400 genes has been documented<ref name=":13" /><ref>{{Cite journal|last=Abraham|first=Roshini S.|last2=Ballman|first2=Karla V.|last3=Dispenzieri|first3=Angela|last4=Grill|first4=Diane E.|last5=Manske|first5=Michelle K.|last6=Price-Troska|first6=Tammy L.|last7=Paz|first7=Natalia Gonzalez|last8=Gertz|first8=Morie A.|last9=Fonseca|first9=Rafael|date=2005|title=Functional gene expression analysis of clonal plasma cells identifies a unique molecular profile for light chain amyloidosis|url=https://ashpublications.org/blood/article/105/2/794/20081/Functional-gene-expression-analysis-of-clonal|journal=Blood|language=en|volume=105|issue=2|pages=794–803|doi=10.1182/blood-2004-04-1424|issn=0006-4971}}</ref><ref>{{Cite journal|last=Davies|first=Faith E.|last2=Dring|first2=Ann M.|last3=Li|first3=Cheng|last4=Rawstron|first4=Andrew C.|last5=Shammas|first5=Masood A.|last6=O'Connor|first6=Sheila M.|last7=Fenton|first7=James A.L.|last8=Hideshima|first8=Teru|last9=Chauhan|first9=Dharminder|date=2003|title=Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis|url=https://ashpublications.org/blood/article/102/13/4504/17472/Insights-into-the-multistep-transformation-of-MGUS|journal=Blood|language=en|volume=102|issue=13|pages=4504–4511|doi=10.1182/blood-2003-01-0016|issn=0006-4971}}</ref>. Of note, individuals with t(11;14) had a lower total overall aberration burden when compared with other AL amyloidosis groups<ref name=":12" />.
===Other Mutations===
Genetic analysis may be used to distinguish AL amyloidosis from hereditary amyloidosis. Testing for mutations in the transthyretin, fibrinogen Aα‐chain, lysozyme or apolipoprotein A-I genes are associated with hereditary disease. Genetic testing is often necessary as clinical features between diseases may be indistinguishable and family history evaluations may not be reflective given reduced penetrance<ref>{{Cite journal|last=Lachmann|first=Helen J.|last2=Booth|first2=David R.|last3=Booth|first3=Susanne E.|last4=Bybee|first4=Alison|last5=Gilbertson|first5=Janet A.|last6=Gillmore|first6=Julian D.|last7=Pepys|first7=Mark B.|last8=Hawkins|first8=Philip N.|date=2002|title=Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis|url=http://www.nejm.org/doi/abs/10.1056/NEJMoa013354|journal=New England Journal of Medicine|language=en|volume=346|issue=23|pages=1786–1791|doi=10.1056/NEJMoa013354|issn=0028-4793}}</ref><ref>{{Cite journal|last=Li|first=Danyang|last2=Liu|first2=Dan|last3=Xu|first3=Hui|last4=Yu|first4=Xiao-juan|last5=Zhou|first5=Fu-de|last6=Zhao|first6=Ming-hui|last7=Wang|first7=Su-xia|date=2019|title=Typing of hereditary renal amyloidosis presenting with isolated glomerular amyloid deposition|url=https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-019-1667-5|journal=BMC Nephrology|language=en|volume=20|issue=1|doi=10.1186/s12882-019-1667-5|issn=1471-2369|pmc=PMC6929319|pmid=31870425}}</ref>.
</blockquote>
==Epigenomic Alterations==
Not applicable
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|EXAMPLE: MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|EXAMPLE: Unregulated cell division
|-
|EXAMPLE: KMT2C and ARID1A; Inactivating mutations
|EXAMPLE: Histone modification, chromatin remodeling
|EXAMPLE: Abnormal gene expression program
|}
==Genetic Diagnostic Testing Methods==
Put your text here
==Familial Forms==
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
==Additional Information==
Put your text here
==Links==
[[Monoclonal Immunoglobulin Deposition Diseases]]
Put your links here (use "Link" icon at top of page)
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
'''
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.
<nowiki>*</nowiki>''Citation of this Page'': “Immunoglobulin-related (AL) amyloidosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Immunoglobulin-related_(AL)_amyloidosis</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases I]]