Compendium of Cancer Genome Aberrations

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CNS5:Medulloblastoma, WNT-activated (view source)

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==Primary Author(s)*==
 
==Primary Author(s)*==
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==Cancer Category/Type==
 
==Cancer Category/Type==
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Medulloblastomas, molecularly defined
    
==Cancer Sub-Classification / Subtype==
 
==Cancer Sub-Classification / Subtype==
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Put your text here
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Medulloblastoma, WNT-activated
    
==Definition / Description of Disease==
 
==Definition / Description of Disease==
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Medulloblastoma is the most common malignant pediatric brain tumor, though it can also occur in adults (PMIDs: 29189165; 23175120; 30445539). Recurrent histopathologic, radiologic, and genomic findings have resulted in the establishment of four primary molecularly-defined subgroups: WNT-activated; SHH-activated and ''TP53''-wildtype; SHH-activated and ''TP53''-mutant; and non-WNT/non-SHH (PMID: 22358457). Somatic variants that cause activation of these pathways (e.g., gain-of-function variants in ''CTNNB1'' for the WNT pathway) are considered diagnostic. Of note, a subset of cases can be due to germline loss-of-function variants in the ''APC'' gene (which also result in activation of WNT signaling), which are representative of the spectrum of disorders known as Familial Adenomatous Polyposis (historically referred to as Gardner syndrome; MIM: 175100). In summary, medulloblastoma, WNT-activated, is an embryonal tumour originating in the dorsal brainstem characterized by activation of the WNT signalling pathway.
    
==Synonyms / Terminology==
 
==Synonyms / Terminology==
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Primitive neuroectodermal tumor of the posterior fossa
    
==Epidemiology / Prevalence==
 
==Epidemiology / Prevalence==
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·      This subtype accounts for approximately 10% of all medulloblastomas (PMIDs: 23175120, 22832581, 22358457, 22134537).
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·      Most frequently observed in older children (median age 10 years; PMIDs: 23175120, 22832581) with a balanced male:female ratio (PMID: 22134537); Of note, this medulloblastoma subtype rarely occurs in infants and rarely metastasizes (PMID: 31799776).
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·      Excellent prognosis for patients <16 years of age at diagnosis: >95% have a five-year overall survival (PMIDs: 16567768; 17172831; 16258095; 19197950)
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·      Accounts for ~15% of all adult medulloblastomas, which may have a worse prognosis than pediatric WNT-activated medulloblastoma (PMID: 28609654, 21632505; 26420814; 27106407)
    
==Clinical Features==
 
==Clinical Features==
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Put your text here and fill in the table
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·      Cranial and spinal MRI are used for diagnosis (PMID: 30765705)
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·      Signs and symptoms (listed below) can increase in severity over weeks to months
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
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|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
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|Headache
 +
 
 +
Clumsiness
 +
 
 +
Fatigue
 +
 
 +
Nausea/vomiting
   −
EXAMPLE B-symptoms (weight loss, fever, night sweats)
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Declining motor skills and/or ataxia
   −
EXAMPLE Fatigue
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Vision problems and/or strabismus
   −
EXAMPLE Lymphadenopathy (uncommon)
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Hydrocephalus
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
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|EXAMPLE Cytopenias
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|None
−
 
  −
EXAMPLE Lymphocytosis (low level)
   
|}
 
|}
    
==Sites of Involvement==
 
==Sites of Involvement==
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·      Cerebellum, cerebellar peduncle or fourth ventricle (PMIDs: 32239782; 26338912)
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·      Origin: cells in the extracerebellar lower rhombic lip (PMID: 21150899)
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·      Metastases are much less likely to occur in this subtype relative to other MB subtypes; staging is performed using the Chang classification (PMID: 4983156)
    
==Morphologic Features==
 
==Morphologic Features==
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·      The WNT-activated subgroup is most commonly observed as an embryonal tumor with classic histology located in the cerebellum and/or fourth ventricle (PMID: 32239782)
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·      Cases generally show a classical histologic pattern:
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o  Small round blue cell tumor
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o   Sheets of densely packed undifferentiated (embryonal) cells
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o   Individual cells with scant cytoplasm, high nuclear-to-cytoplasmic ratio, and salt-and-pepper chromatin
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o   Presence of mitoses, apoptotic bodies, and Homer Wright rosettes
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·      High degree of hemorrhage relative to other subtypes
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·      Rare examples with anaplastic histology have been described (PMIDs: 21267586; 31104222)
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·      Activated WNT pathway signaling - commonly visualized by immunohistochemical studies showing nuclear beta-catenin staining
    
==Immunophenotype==
 
==Immunophenotype==
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·      Majority positive for synaptophysin; INI-1 staining should be retained (positive)
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·      Molecular subtyping may be performed immunohistochemically using Filamin A, YAP1, GAB1 and beta-catenin (PMIDs: 32239782, 21267586)
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Finding!!Marker
 
!Finding!!Marker
 
|-
 
|-
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|Positive (universal)||EXAMPLE CD1
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|'''Positive (universal)'''
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|Nuclear beta-catenin, Filamin A, and YAP1
 
|-
 
|-
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|Positive (subset)||EXAMPLE CD2
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|'''Positive (subset)'''
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|
 
|-
 
|-
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|Negative (universal)||EXAMPLE CD3
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|'''Negative (universal)'''
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|GAB1
 
|-
 
|-
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|Negative (subset)||EXAMPLE CD4
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|'''Negative (subset)'''
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|YAP1 (in areas of heavy neuronal differentiation)
 
|}
 
|}
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!Notes
 
!Notes
 
|-
 
|-
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|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
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|'''Chromosomal Rearrangement'''
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EXAMPLE 30% (add reference)
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|'''Genes in Fusion'''
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|Yes
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|No
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'''(5’ or 3’ Segments)'''
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|Yes
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|'''Pathogenic Derivative'''
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|EXAMPLE
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|'''Prevalence'''
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|'''Diagnostic Significance (Yes, No or  Unknown)'''
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|'''Prognostic Significance (Yes, No or  Unknown)'''
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|'''Therapeutic Significance (Yes, No or  Unknown)'''
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|'''Notes'''
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|-
 +
|RAP1A-TMIGD3
 +
 
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1p13.2; 1p13.2
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|Unknown
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|Unknown
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|Rare (estimated ≤5% of medulloblastoma)
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|Unknown
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|Unknown
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|Unknown
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|PMID: 33681213
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|-
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|ARID1A-PHACTR4
   −
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).
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1p36.11; 1p35.3
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|ARID1A (5’); PHACTR4 (3’)
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|Exons 1-4 ARID1A; Exons 11-15 PHACTR4
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|Rare (estimated ≤2% of medulloblastoma)
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|Unknown
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|Unknown
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|Unknown
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|PMID: 33681213
 
|}
 
|}
 
 
 
==Individual Region Genomic Gain/Loss/LOH==
 
==Individual Region Genomic Gain/Loss/LOH==
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·      Monosomy 6 is the most frequently reported genomic alteration, occurring within 80-85% of cases and commonly co-occurring with ''CTNNB1'' somatic mutations. (PMIDs: 16567768; 28726821; 17172831; 30765705)
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·      With the exception of monosomy 6, this medulloblastoma subtype usually has a balanced genome (PMID: 22832581)
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
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!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
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|6
−
 
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|Loss
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7
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|Chr6:1-170,805,979- [hg38]
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|EXAMPLE Loss
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|Chr6
−
|EXAMPLE
  −
 
  −
chr7:1- 159,335,973 [hg38]
  −
|EXAMPLE
  −
 
  −
chr7
   
|Yes
 
|Yes
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|Yes
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|Yes – Monosomy 6 is associated with very good outcome in pediatric  patients (PDQ, PMIDs: 24791927, 21267586, 17012043).
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|No
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|No<span lang="EN-US">Medulloblastomas,
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|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).
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molecularly defined
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|-
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|Presence of monosomy 6 is frequently observed, and present in  80-90% of cases (PMID: 28726821).  This finding is much more common in pediatric patients and has been proposed  as a marker for WNT subtype α.  
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|EXAMPLE
     −
8
  −
|EXAMPLE Gain
  −
|EXAMPLE
     −
chr8:1-145,138,636 [hg38]
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However, absence of monosomy 6 does not rule out the possibility  of WNT-activated medulloblastoma (PMID: 28726821).  Furthermore, adult patients will be misdiagnosed if monosomy 6 is used  alone as a diagnostic factor, as they cluster within WNT subtype β, which  characteristically lacks this finding (PMID: 28609654).
−
|EXAMPLE
     −
chr8
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|No
  −
|No
  −
|No
  −
|EXAMPLE
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Common recurrent secondary finding for t(8;21) (add reference).
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Outside of monosomy 6, other cytogenetic findings are rarely  observed in this subtype (PMID: 23175120).
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|-
 +
| colspan="8" |
 
|}
 
|}
 
==Characteristic Chromosomal Patterns==
 
==Characteristic Chromosomal Patterns==
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N/A
−
 
+
==Gene Mutations (SNV/INDEL)==
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{| class="wikitable sortable"
  −
|-
  −
!Chromosomal Pattern
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!Diagnostic Significance (Yes, No or Unknown)
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!Prognostic Significance (Yes, No or Unknown)
  −
!Therapeutic Significance (Yes, No or Unknown)
  −
!Notes
  −
|-
  −
|EXAMPLE
     −
Co-deletion of 1p and 18q
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·      Characterized by constitutive activation of the WNT signaling pathway. This occurs in approximately 85-90% of WNT-subtype medulloblastomas via somatic, gain-of-function, mutations in exon 3 of the ''CTNNB1'' gene (PMID: 30765705).
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|Yes
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|No
  −
|No
  −
|EXAMPLE:
     −
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
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·      Patients without activating ''CTNNB1'' somatic mutations often have germline loss-of-function variants in ''APC'', which then also lead to constitutively increased WNT pathway signaling (PMID: 29753700)
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|}
  −
==Gene Mutations (SNV/INDEL)==
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  −
Put your text here and fill in the table
      +
·      The WNT-subtype has the second highest somatic single nucleotide burden of all subgroups with ~1,800 per genome. ''DDX3X'', ''SMARCA4'', ''TP53'', ''CSNK2B'', ''PIK3CA'', and ''EPHA7'' are among the most recurrently mutated genes (PMIDs: 28726821; 22832583, 22820256, 22722829)
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
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!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE: TP53; Variable LOF mutations
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|''CTNNB1''; Activating;  Exon 3
 +
|Oncogene
 +
|85% (WNT-subtype medulloblastoma cases in COSMIC)
 +
|Often observed with monosomy 6
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|''APC''
 +
|Yes
 +
|Yes – Favorable prognosis (PMID: 31504825)
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|No
 +
|~85% of cases (PMID: 28726821);  Somatic
 +
|-
 +
|''APC'';  
   −
EXAMPLE:
+
Loss of Function
−
 
+
|Tumor suppressor
−
EGFR; Exon 20 mutations
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|5-10% (COSMIC; PMID: 28726821)
−
 
  −
EXAMPLE: BRAF; Activating mutations
  −
|EXAMPLE: TSG
  −
|EXAMPLE: 20% (COSMIC)
  −
 
  −
EXAMPLE: 30% (add Reference)
  −
|EXAMPLE: IDH1 R123H
  −
|EXAMPLE: EGFR amplification
   
|
 
|
 +
|''CTNNB1''
 
|
 
|
 +
|Yes – Favorable prognosis (PMID: 31504825)
 
|
 
|
−
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
+
|Warrant germline evaluation if identified (PMID: 32239782, 28726821); LOF of APC  leads to nuclear accumulation of β-catenin, resulting in increased WNT signaling (PMID: 29189165)
−
<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.
 
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.
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==Epigenomic Alterations==
 
==Epigenomic Alterations==
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Approximately one third of medulloblastomas across all subgroups carry mutations in histone modifier genes, however, they are not unique to the WNT subtype (PMID: 29189165).
    
==Genes and Main Pathways Involved==
 
==Genes and Main Pathways Involved==
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·      Canonical WNT-pathway activation (PMID: 31921137)
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
−
|EXAMPLE: BRAF and MAP2K1; Activating mutations
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|''CTNNB1''; Activating mutations in exon 3 (especially at amino acid residues p.D32, p.S33, p.G34,  and p.S37; COSMIC, PeCAN)
−
|EXAMPLE: MAPK signaling
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|Canonical WNT-signaling
−
|EXAMPLE: Increased cell growth and proliferation
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|Promotes cell proliferation and differentiation
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 +
Promotes immune tolerance
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 +
Promotes epithelial-mesenchymal transition
 
|-
 
|-
−
|EXAMPLE: CDKN2A; Inactivating mutations
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| colspan="3" |
−
|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==
 
==Genetic Diagnostic Testing Methods==
   −
Put your text here
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·      Chromosomes– assess for monosomy 6 (PMIDs: 32239782, 29027579)
 +
 
 +
·      Chromosomal Microarray – assess for monosomy 6
 +
 
 +
·      Sequence analysis (e.g. NGS) – assess for somatic mutations in ''CTNNB1'' and/or ''APC''
 +
 
 +
·      DNA methylation profiling – tumor type and subtype classification by epigenetic signatures
 +
 
 +
·      Transcriptomics – tumor type and subtype classification by gene expression signatures
    
==Familial Forms==
 
==Familial Forms==
   −
Put your text here
+
·      Germline variants in ''APC'', which most commonly cause Familial Adenomatous Polyposis, may also lead to the development of WNT-activated subtype medulloblastoma (PMIDs: 32239782, 30765705)
    
==Additional Information==
 
==Additional Information==
   −
Put your text here
+
·      DNA methylation profiling is considered to be the current gold-standard for determining MB subgroup and subtype (PMIDs: 23670100; 23291781) and is available clinically
 +
 
 +
·      Good prognosis is currently thought to be due to alterations in tumour vasculature and its effects on the blood-brain barrier, making the tumor more accessible to systemic chemotherapies (PMID: 27050100)
 +
 
 +
·      Somatic ''TP53'' mutations do not portend a worse prognosis (PMID: 23835706)
 +
 
 +
·      Recent studies employing single-cell RNA-seq (PMID: 31341285) are revealing transcriptional and genetic heterogeneity within this and other MB subgroups
    
==Links==
 
==Links==
   −
Put your text placeholder here (use "Link" icon at top of page)
+
*''[https://pecan.stjude.cloud/proteinpaint/ctnnb1 CTNNB1 entry in PeCAN]''
 +
*''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?coords=AA%3AAA&sn=central_nervous_system&ss=brain&hn=primitive_neuroectodermal_tumour-medulloblastoma&sh=WNT_subtype&wgs=off&id=141847&ln=CTNNB1&start=1&end=782 CTNNB1 entry in COSMIC (WNT-activated medulloblastoma)]''
 +
 
 +
<br />
    
==References==
 
==References==
 
<references />
 
<references />
−
(use "Cite" icon at top of page)
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1.      Ellison, DW, Korshunov A, Northcott PA, Taylor MD, Kaur K, Clifford SC. Medulloblastoma, WNT-activated. In: WHO Classification of Tumours Editorial Board. Central nervous system tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 6). <nowiki>https://publications.iarc.fr/601</nowiki>.
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===EXAMPLE Book===
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2.      PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Cancer Genomics. Bethesda, MD: National Cancer Institute. Updated 12/28/2021. Available at: <nowiki>https://www.cancer.gov/types/childhood-cancers/pediatric-genomics-hp-pdq</nowiki>. Accessed 01/28/2022 [PMID: 27466641]
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3.      Khatua S, Song A, Citla Sridhar D, Mack SC. Childhood Medulloblastoma: Current Therapies, Emerging Molecular Landscape and Newer Therapeutic Insights. Curr Neuropharmacol. 2018;16(7):1045-1058. doi: 10.2174/1570159X15666171129111324. PMID: 29189165
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4.      Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. Neuro Oncol. 2018 Oct 1;20(suppl_4):iv1-iv86. doi: 10.1093/neuonc/noy131. Erratum in: Neuro Oncol. 2018 Nov 17. PMID: 30445539
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5.      Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, Pomeroy SL, Korshunov A, Lichter P, Taylor MD, Pfister SM. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012 Dec;12(12):818-34. doi: 10.1038/nrc3410. PMID: 23175120
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6.      Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li Y, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AG, Thiessen NT, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H, Fernandez-L A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fèvre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EM, Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss WA, Bognár L, Klekner A, Van Meter TE, Kumabe T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser P, Saad AG, Iolascon A, Jung S, Carlotti CG, Vibhakar R, Ra YS, Robinson S, Zollo M, Faria CC, Chan JA, Levy ML, Sorensen PH, Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U, Hawkins CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJ, Korbel JO, Pfister SM, Marra MA, Taylor MD. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012 Aug 2;488(7409):49-56. doi: 10.1038/nature11327. PMID: 22832581
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 +
7.      Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, Bäcklund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012 Apr;123(4):473-84. doi: 10.1007/s00401-012-0958-8. Epub 2012 Feb 23. PMID: 22358457
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 +
8.      Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012 Apr;123(4):465-72. doi: 10.1007/s00401-011-0922-z. Epub 2011 Dec 2. PMID: 22134537
 +
 
 +
9.      Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ, Taylor MD, Curran T, Gajjar A, Gilbertson RJ. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol. 2006 Apr 20;24(12):1924-31. doi: 10.1200/JCO.2005.04.4974. Epub 2006 Mar 27. PMID: 16567768.
 +
 
 +
10.  Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D, Ellison DW. Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle. 2006 Nov;5(22):2666-70. doi: 10.4161/cc.5.22.3446. Epub 2006 Nov 15. PMID: 17172831.
 +
 
 +
11.  Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, Pearson AD, Clifford SC; United Kingdom Children's Cancer Study Group Brain Tumour Committee. beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol. 2005 Nov 1;23(31):7951-7. doi: 10.1200/JCO.2005.01.5479. PMID: 16258095.
 +
 
 +
12.  Fattet S, Haberler C, Legoix P, Varlet P, Lellouch-Tubiana A, Lair S, Manie E, Raquin MA, Bours D, Carpentier S, Barillot E, Grill J, Doz F, Puget S, Janoueix-Lerosey I, Delattre O. Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics. J Pathol. 2009 May;218(1):86-94. doi: 10.1002/path.2514. PMID: 19197950.
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==Notes==
 
==Notes==
 
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<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.
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