Rare germline variants in the AXIN2 gene in families with colonic polyposis and colorectal cancer.
AXIN2
Colonic polyposis
Colorectal cancer
Ectodermal dysplasia
Oligodontia
Journal
Familial cancer
ISSN: 1573-7292
Titre abrégé: Fam Cancer
Pays: Netherlands
ID NLM: 100898211
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
24
07
2021
accepted:
08
11
2021
pubmed:
25
11
2021
medline:
9
11
2022
entrez:
24
11
2021
Statut:
ppublish
Résumé
Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2). Variant segregation in relatives and characterisation of tumour tissue were performed where possible. Four different germline pathogenic variants in AXIN2 were identified in four families. Five of the seven carriers of the c.1049delC, p.Pro350Leufs*13 variant, two of the six carriers of the c.1994dupG, p.Asn666Glnfs*41 variant, all three carriers of c.1972delA, p.Ser658Alafs*31 variant and the single proband carrier of the c.2405G>C, p.Arg802Thr variant, which creates an alternate splice form resulting in a frameshift mutation (p.Glu763Ilefs*42), were affected by CRC and/or polyposis. Carriers had a mean age at diagnosis of CRC/polyposis of 52.5 ± 9.2 years. Colonic polyps were typically pan colonic with counts ranging from 5 to >100 (median 12.5) comprising predominantly adenomatous polyps but also serrated polyps. Two CRCs from carriers displayed evidence of a second hit via loss of heterozygosity. Oligodontia was observed in carriers from two families. Germline AXIN2 pathogenic variants from four families were associated with CRC and/or polyposis in multiple family members. These findings support the inclusion of AXIN2 in CRC and polyposis multigene panels for clinical testing.
Identifiants
pubmed: 34817745
doi: 10.1007/s10689-021-00283-9
pii: 10.1007/s10689-021-00283-9
doi:
Substances chimiques
AXIN2 protein, human
0
Axin Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
399-413Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature B.V.
Références
Lorans M, Dow E, Macrae FA, Winship IM, Buchanan DD (2018) Update on hereditary colorectal cancer: improving the clinical utility of multigene panel testing. Clin Colorectal Cancer 17(2):e293–e305. https://doi.org/10.1016/j.clcc.2018.01.001
doi: 10.1016/j.clcc.2018.01.001
pubmed: 29454559
Seidensticker MJ, Behrens J (2000) Biochemical interactions in the Wnt pathway. Biochim Biophys Acta 1495(2):168–182
doi: 10.1016/S0167-4889(99)00158-5
pubmed: 10656974
Powell SM, Zilz N, Beazer-Barclay Y et al (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359(6392):235–7
doi: 10.1038/359235a0
pubmed: 1528264
Behrens J, Jerchow BA, Wurtele M et al (1998) Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 280(5363):596–9
doi: 10.1126/science.280.5363.596
pubmed: 9554852
Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F (2002) Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22(4):1172–1183
doi: 10.1128/MCB.22.4.1172-1183.2002
pubmed: 11809808
pmcid: 134648
Lammi L, Arte S, Somer M et al (2004) Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 74(5):1043–1050
doi: 10.1086/386293
pubmed: 15042511
pmcid: 1181967
Renkonen ET, Nieminen P, Abdel-Rahman WM et al (2005) Adenomatous polyposis families that screen APC mutation-negative by conventional methods are genetically heterogeneous. J Clin Oncol 23(24):5651–9
doi: 10.1200/JCO.2005.14.712
pubmed: 16110024
Bergendal B, Klar J, Stecksen-Blicks C, Norderyd J, Dahl N (2011) Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes. Am J Med Genet A 155A(7):1616–1622. https://doi.org/10.1002/ajmg.a.34045
doi: 10.1002/ajmg.a.34045
pubmed: 21626677
Marvin ML, Mazzoni SM, Herron CM, Edwards S, Gruber SB, Petty EM (2011) AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome. Am J Med Genet A 155A(4):898–902. https://doi.org/10.1002/ajmg.a.33927
doi: 10.1002/ajmg.a.33927
pubmed: 21416598
Rivera B, Perea J, Sanchez E et al (2014) A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia. Eur J Hum Genet 22(3):423–6. https://doi.org/10.1038/ejhg.2013.146
doi: 10.1038/ejhg.2013.146
pubmed: 23838596
Buchanan DD, Clendenning M, Zhuoer L et al (2017) Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study. Gut 66(6):1170–2. https://doi.org/10.1136/gutjnl-2016-312773
doi: 10.1136/gutjnl-2016-312773
pubmed: 27582512
Snover D (2010) Serrated polyps of the colon and rectum and serrated polyposis. In: WHO classification of tumours of the digestive system. IARC, Lyon, pp 160–165
Rosty CBL, Dekker E, Nagtegaal ID (2019) Serrated polyposis. In: WHO classification of tumours of the digestive system. IARC, Lyon, pp 532–544
McLaren W, Gil L, Hunt SE et al (2016) The Ensembl variant effect predictor. Genome Biol 17(1):122. https://doi.org/10.1186/s13059-016-0974-4
doi: 10.1186/s13059-016-0974-4
pubmed: 27268795
pmcid: 4893825
Karczewski KJ, Francioli LC, Tiao G et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581(7809):434–443
doi: 10.1038/s41586-020-2308-7
pubmed: 32461654
pmcid: 7334197
Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M (2019) CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47(D1):D886–D894. https://doi.org/10.1093/nar/gky1016
doi: 10.1093/nar/gky1016
pubmed: 30371827
Ioannidis NM, Rothstein JH, Pejaver V et al (2016) REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 99(4):877–885. https://doi.org/10.1016/j.ajhg.2016.08.016
doi: 10.1016/j.ajhg.2016.08.016
pubmed: 27666373
pmcid: 5065685
Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30
doi: 10.1038/gim.2015.30
pubmed: 25741868
pmcid: 4544753
Kopanos C, Tsiolkas V, Kouris A et al (2019) VarSome: the human genomic variant search engine. Bioinformatics 35(11):1978–1980. https://doi.org/10.1093/bioinformatics/bty897
doi: 10.1093/bioinformatics/bty897
pubmed: 30376034
El-Gebali S, Mistry J, Bateman A et al (2019) The Pfam protein families database in 2019. Nucleic Acids Res 47(D1):D427–D432. https://doi.org/10.1093/nar/gky995
doi: 10.1093/nar/gky995
pubmed: 30357350
Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30(15):2114–2120. https://doi.org/10.1093/bioinformatics/btu170
doi: 10.1093/bioinformatics/btu170
pubmed: 24695404
pmcid: 4103590
Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25(14):1754–1760. https://doi.org/10.1093/bioinformatics/btp324
doi: 10.1093/bioinformatics/btp324
pubmed: 19451168
pmcid: 2705234
Cibulskis K, Lawrence MS, Carter SL et al (2013) Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31(3):213–9. https://doi.org/10.1038/nbt.2514
doi: 10.1038/nbt.2514
pubmed: 23396013
pmcid: 3833702
Kim S, Scheffler K, Halpern AL et al (2018) Strelka2: fast and accurate calling of germline and somatic variants. Nat Methods 15(8):591–4. https://doi.org/10.1038/s41592-018-0051-x
doi: 10.1038/s41592-018-0051-x
pubmed: 30013048
Beard C, Purvis R, Winship IM, Macrae FA, Buchanan DD (2019) Phenotypic confirmation of oligodontia, colorectal polyposis and cancer in a family carrying an exon 7 nonsense variant in the AXIN2 gene. Fam Cancer 18(3):311–5. https://doi.org/10.1007/s10689-019-00120-0
doi: 10.1007/s10689-019-00120-0
pubmed: 30671715
Liu W, Dong X, Mai M et al (2000) Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat Genet 26(2):146–7
doi: 10.1038/79859
pubmed: 11017067
Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–7. https://doi.org/10.1038/nature11252
doi: 10.1038/nature11252
Otero L, Lacunza E, Vasquez V, Arbelaez V, Cardier F, Gonzalez F (2019) Variations in AXIN2 predict risk and prognosis of colorectal cancer. BDJ Open 5:13. https://doi.org/10.1038/s41405-019-0022-z
doi: 10.1038/s41405-019-0022-z
pubmed: 31632692
pmcid: 6795800
Macklin-Mantia SK, Hines SL, Chaichana KL et al (2020) Case report expanding the germline AXIN2-related phenotype to include olfactory neuroblastoma and gastric adenoma. BMC Med Genet 21(1):161. https://doi.org/10.1186/s12881-020-01103-0
doi: 10.1186/s12881-020-01103-0
pubmed: 32807118
pmcid: 7433097
Wong S, Liu H, Bai B et al (2014) Novel missense mutations in the AXIN2 gene associated with non-syndromic oligodontia. Arch Oral Biol 59(3):349–353. https://doi.org/10.1016/j.archoralbio.2013.12.009
doi: 10.1016/j.archoralbio.2013.12.009
pubmed: 24581859