Abstract
We present a three-generation family with an AXIN2 variant and a family history of colorectal cancer (CRC), colon polyps and tooth agenesis. A likely pathogenic variant was detected in the AXIN2 gene (c.1994dup; p.(Asn666Glnfs*41)). This variant has previously been associated with tooth agenesis and polyposis, only. In this case report we describe eight carriers with tooth agenesis and variable clinical findings, including polyps and CRC. Our case provides additional knowledge to the sparse data on genotype–phenotype association related to AXIN2 associated cancer syndrome. Further, our case highlights the importance of analysing an extended CRC and oligodontia/ectodermal dysplasia gene panel including AXIN2 but also raises awareness and discussion about appropriate surveillance program.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
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. https://doi.org/10.1086/386293
Rivera B, Perea J, Sánchez 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):423–426. https://doi.org/10.1038/ejhg.2013.146
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
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):311–315. https://doi.org/10.1007/s10689-019-00120-0
Dong X, Seelan RS, Qian C, Mai M, Liu W (2001) Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene. Cytogenet Cell Genet 93(1–2):26–28. https://doi.org/10.1159/000056942
Behrens J, Jerchow BA, Würtele M et al (1998) Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 280(5363):596–599. https://doi.org/10.1126/science.280.5363.596
Akiyama T (2000) Wnt/beta-catenin signaling. Cytokine Growth Factor Rev 11(4):273–282. https://doi.org/10.1016/s1359-6101(00)00011-3
MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26. https://doi.org/10.1016/j.devcel.2009.06.016
Willert K, Nusse R (1998) Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev 8(1):95–102. https://doi.org/10.1016/s0959-437x(98)80068-3
Nunn JH, Carter NE, Gillgrass TJ et al (2003) The interdisciplinary management of hypodontia: background and role of paediatric dentistry. Br Dent J 194(5):245–251. https://doi.org/10.1038/sj.bdj.4809925
Li MM, Datto M, Duncavage EJ et al (2017) Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, american society of clinical oncology, and college of american pathologists. J Mol Diagn 19(1):4–23. https://doi.org/10.1016/j.jmoldx.2016.10.002
Bergendal B, Klar J, Stecksén-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
Macklin-Mantia SK, Riegert-Johnson DL (2020) An American patient with polyposis carrying a Scandinavian. Hered Cancer Clin Pract 18:14. https://doi.org/10.1186/s13053-020-00149-8
Rohlin A, Rambech E, Kvist A et al (2017) Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing. Fam Cancer 16(2):195–203. https://doi.org/10.1007/s10689-016-9934-0
Hansen MF, Johansen J, Sylvander AE et al (2017) Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome. Clin Genet 92(4):405–414. https://doi.org/10.1111/cge.12994
Lamba A, Oarekh P, Dvorak CT, Karlitz JJ (2018) Pedigree analysis supports a correlation between an AXIN2 variant and polyposis/colorectal cancer. World J Med Gen 8(1):1–4
Liu H, Ding T, Zhan Y, Feng H (2015) A novel AXIN2 missense mutation is associated with non-syndromic oligodontia. PLoS One 10(9):e0138221. https://doi.org/10.1371/journal.pone.0138221
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
Hlouskova A, Bielik P, Bonczek O, Balcar VJ, Šerý O (2017) Mutations in AXIN2 gene as a risk factor for tooth agenesis and cancer: a review. Neuro Endocrinol Lett 38(3):131–137
Dai J, Gao H, Xue J, Lin W, Zheng L (2019) The association between AXIN2 gene polymorphisms and the risk of breast cancer in chinese women. Genet Test Mol Biomarkers 23(6):393–400. https://doi.org/10.1089/gtmb.2018.0309
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
Network NCC (2017) NCCN guidelines. Genetic/familial high-risk assessment: colorectalcancer
(DKS) DSoMGDaDSS (2020) Guideline: examination and follow-up for hereditary polypose syndromes (Udredning og opfølgning for arvelige polyposesyndromer)
Funding
No funds, grants or other support was received.
Author information
Authors and Affiliations
Contributions
JMJ, AS, LS and CKL conceptualized and drafted the initial manuscript, reviewed, and revised the manuscript. HG and MS participated with clinical information, drafts of figures and critically reviewed the manuscript for important intellectual content. KL critically reviewed the manuscript for important intellectual content. MG performed and analysed the sequencing and reviewed the manuscript. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare to have no financial or non-financial relationships relevant to this article to disclose.
Ethical approval
Approvement from national ethics comity not needed.
Consent to participate
Informed consent was obtained from all participants.
Consent for publication
All participants signed informed consent regarding publishing their data.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Jensen, J.M., Skakkebæk, A., Gaustadness, M. et al. Familial colorectal cancer and tooth agenesis caused by an AXIN2 variant: how do we detect families with rare cancer predisposition syndromes?. Familial Cancer 21, 325–332 (2022). https://doi.org/10.1007/s10689-021-00280-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-021-00280-y