Compendium of Cancer Genome Aberrations

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ASXL1 (view source)

Revision as of 18:29, 5 January 2019

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==Primary Author(s)*==
 
==Primary Author(s)*==
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Kay Weng Choy MBBS
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Kay Weng Choy, MBBS, Monash Medical Centre
    
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__TOC__
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'''Cytoband:''' 20q11.21
 
'''Cytoband:''' 20q11.21
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'''Genomic Coordinates:'''  
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'''Genomic Coordinates:'''
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Put your text here
      
chr20:32,358,330-32,439,319 (GRCh38/hg38)
 
chr20:32,358,330-32,439,319 (GRCh38/hg38)
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Stem cell transplantation is recommended in patients with PMF with presence of mutational status CALR-/ASXL+, as the mutational status is associated with a worse prognosis [21].  
 
Stem cell transplantation is recommended in patients with PMF with presence of mutational status CALR-/ASXL+, as the mutational status is associated with a worse prognosis [21].  
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''Colorectal cancer''
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''Colorectal cancer (CRC)''
    
ASXL1 is frequently mutated in colorectal cancer cell lines with microsatellite instability (MSI) [22]. The G8 mononucleotide repeat at nucleotide position c.1927 to c.1934 of the ASXL1 gene is susceptible to the deletion or insertion of a G nucleotide as a result of MSI [22]. The deletion of c.1934G (c.1934delG) causes a frameshift and the insertion of G between c.1934 and c.1935 (c.1934_1935insG) causes a frameshift [22]. The c.1934_1935insG ASXL1 mutation is reported to be resistant to nonsense-mediated decay in CRC with MSI and consequently is predicted to be expressed as a C-terminally truncated protein [22].
 
ASXL1 is frequently mutated in colorectal cancer cell lines with microsatellite instability (MSI) [22]. The G8 mononucleotide repeat at nucleotide position c.1927 to c.1934 of the ASXL1 gene is susceptible to the deletion or insertion of a G nucleotide as a result of MSI [22]. The deletion of c.1934G (c.1934delG) causes a frameshift and the insertion of G between c.1934 and c.1935 (c.1934_1935insG) causes a frameshift [22]. The c.1934_1935insG ASXL1 mutation is reported to be resistant to nonsense-mediated decay in CRC with MSI and consequently is predicted to be expressed as a C-terminally truncated protein [22].
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The majority of ASXL1 mutations are nonsense or frameshift variants causing truncation of downstream of the ASXH domain with consequent loss of the PHD domain [1]. Some of the common variants reported in the Catalogue of Somatic Mutations in Cancer database (COSMIC) (accessed 6th August 2018) are c.2444T>C (NM_015338.5) (p.L815P) (n=97) (all AML), c.2077C>T (NM_015338.5) (p.R693*) (majority hematological malignancies), c.1934_1935insG (NM_015338.5) (p.G646Wfs*12) (majority hematological malignancies).
 
The majority of ASXL1 mutations are nonsense or frameshift variants causing truncation of downstream of the ASXH domain with consequent loss of the PHD domain [1]. Some of the common variants reported in the Catalogue of Somatic Mutations in Cancer database (COSMIC) (accessed 6th August 2018) are c.2444T>C (NM_015338.5) (p.L815P) (n=97) (all AML), c.2077C>T (NM_015338.5) (p.R693*) (majority hematological malignancies), c.1934_1935insG (NM_015338.5) (p.G646Wfs*12) (majority hematological malignancies).
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{| class="wikitable sortable"
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! Copy Number Loss  !! Copy Number Gain  !!  LOH  !!  Loss-of-Function Mutation  !!  Gain-of-Function Mutation  !!  Translocation/Fusion
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==Internal Pages==
 
==Internal Pages==
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Put your text here
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N/A
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EXAMPLE [[Germline Cancer Predisposition Genes]]
      
==External Links==
 
==External Links==
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Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.
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[http://atlasgeneticsoncology.org/Genes/ASXL1ID44553ch20q11.html ASXL1 by Atlas of Genetics and Cytogenetics in Oncology – detailed gene information]
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[https://cancer.sanger.ac.uk/cosmic/search?q=ASXL1 ASXL1 by COSMIC – sequence information, expression, catalogue of mutations]
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[https://civicdb.org/events/genes/68/summary/variants/177/summary ASXL1 by CIViC – general knowledge and evidence-based specific information]
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[https://pmkb.weill.cornell.edu/search?utf8=%E2%9C%93&search=ASXL1 ASXL1 by Precision Medicine Knowledgebase (Weill Cornell) – manually vetted interpretations of variants and CNVs]
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[http://www.cancerindex.org/geneweb/ASXL1.htm ASXL1 by Cancer Genetics Web – gene, pathway, and publication information matched to cancer type]
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EXAMPLES
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[http://oncokb.org/#/gene/ASXL1effect, variant classification ASXL1 by OncoKB – mutational landscape, mutation effect, variant classification]
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'''[http://atlasgeneticsoncology.org/Genes/P53ID88.html ''TP53'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
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[https://www.mycancergenome.org/content/gene/ASXL1 ASXL1 by My Cancer Genome – brief gene overview]
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'''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=TP53 ''TP53'' by COSMIC]''' - sequence information, expression, catalogue of mutations
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[https://www.uniprot.org/uniprot/Q8IXJ9 ASXL1 by UniProt – protein and molecular structure and function]
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'''[https://civicdb.org/events/genes/45/summary/variants/1300/summary ''TP53'' by CIViC]''' - general knowledge and evidence-based variant specific information
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[https://pfam.xfam.org/search/keyword?query=ASXL1+ ASXL1 by Pfam – gene and protein structure and function information]
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'''[http://p53.iarc.fr/ ''TP53'' by IARC]''' - ''TP53'' database with reference sequences and mutational landscape
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[https://www.genecards.org/cgi-bin/carddisp.pl?gene=ASXL1&keywords=ASXL1 ASXL1 by GeneCards – general gene information and summaries]
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'''[https://pecan.stjude.cloud/proteinpaint/tp53 ''TP53'' by St. Jude ProteinPaint]''' mutational landscape and matched expression data.
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==References==
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'''[https://pmkb.weill.cornell.edu/search?utf8=%E2%9C%93&search=tp53 ''TP53'' by Precision Medicine Knowledgebase (Weill Cornell)]''' - manually vetted interpretations of variants and CNVs
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1. Alvarez Argote J, Dasanu CA, (2018). ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival. Curr Med Red Opin 34(5):757-763. PMID 28027687
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'''[http://www.cancerindex.org/geneweb/TP53.htm ''TP53'' by Cancer Index]''' - gene, pathway, publication information matched to cancer type
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2. Jacobs JJ, van Lohuizen M, (2002). Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta 1602(2):151-61. PMID 12020801
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'''[http://oncokb.org/#/gene/TP53 ''TP53'' by OncoKB]''' - mutational landscape, mutation effect, variant classification
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3. Xiong B, et al., (2014). Characterization of side population cells isolated from the colon cancer cell line SW480. Int J Oncol 45(30:1175-1183. PMID 24926880
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'''[https://www.mycancergenome.org/content/gene/tp53/ ''TP53'' by My Cancer Genome]''' - brief gene overview
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4. Fisher CL, et al., (2006). Characterization of Asxl1, a murine homolog of Additional sex combs, and analysis of the Asx-like gene family. Gene 369:109-118. PMID 16412590
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'''[http://www.uniprot.org/uniprot/P04637 ''TP53'' by UniProt]''' - protein and molecular structure and function
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5. Gelsi-Boyer V, et al., (2009). Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 145:788-800. PMID 19388938
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'''[https://pfam.xfam.org/family/p53 ''TP53'' by Pfam]''' - gene and protein structure and function information
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6. Carbuccia N, et al., (2009). Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 23(11);2183-2186. PMID 19609284
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'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=tp53 ''TP53'' by GeneCards]''' - general gene information and summaries
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7. Abdel-Wahab O, et al., (2012). ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 22(20):180-193. PMID 22897849
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'''[https://www.ncbi.nlm.nih.gov/books/NBK1311/ GeneReviews]''' - information on Li Fraumeni Syndrome
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8. Lindsley RC, et al., (2015). Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125(9):1367-1376. PMID 25550361
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==References==
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9. Schnittger S, et al., (2013). ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 27(1):82-91. PMID 23018865
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10. Shen H, et al., (2015). CALR and ASXL1 mutation analysis in 190 patients with essential thrombocythemia. Leuk Lymphoma 56(3):820-822. PMID 25005031
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11. Pellagatti A, et al., (2016). Targeted resequencing analysis of 31 genes commonly mutated in myeloid disorders in serial samples from myelodysplastic syndrome patients showing disease progression. Leukemia 30(10:247-250. PMID 25991409
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12. Chou WC, et al., (2010). Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like (ASXL1) mutations. Blood 116(20):4086-4094. PMID 20693432
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13. Devillier R, et al., (2015). Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasic-related changes. Oncotarget 2015;6(10:8388-8396. PMID 25860933
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14. Patnaik MM, et al., (2014). ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia 28(11):2206-2212. PMID 24695057
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15. Patnaik MM, et al., (2013). Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 27(7):1504-1510. PMID 23531518
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16. Chen TC, et al., (2014). Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome. Blood Cancer J 4:e177. PMID 24442206
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17. Thol F, et al., (2011). Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol 29(18):2499-2506. PMID 21576631
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18. Papaemmanuil E, et al., (2016). Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374(23):2209-2221. PMID 27276561
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19. Itzykson R, et al., (2013). Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 31(19):2428-2436. PMID 23690417
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20. Metzeler KH, et al., (2011). ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood 118(26):6920-6929. PMID 22031865
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=== EXAMPLE Book ===
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21. Tefferi A, et al., (2014). Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 89(9):915-925. PMID 25124313
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#Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.
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=== EXAMPLE Journal Article ===
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22. Williams DS, et al., (2010). Nonsense mediated decay resistant mutations are a source of expressed mutant proteins in colon cancer cell lines with microsatellite instability. PLoS One 5(12):e16012. PMID 21209843
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#Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.
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== Notes ==
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==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>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.
    
[[Category:Cancer Genes A]]
 
[[Category:Cancer Genes A]]
Kay.Choy
49

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