Familial colorectal cancer and tooth agenesis caused by an AXIN2 variant: how do we detect families with rare cancer predisposition syndromes?

Jensen, Janni M; Skakkebæk, Anne; Gaustadness, Mette; Sommerlund, Mette; Gjørup, Hans; Ljungmann, Ken; Lautrup, Charlotte Kvist; Sunde, Lone

doi:10.1007/s10689-021-00280-y

Cited by 7 publications

(8 citation statements)

References 20 publications

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Section: Discussionsupporting

confidence: 88%

“…However, given the young age of these patients at genetic diagnosis, predisposition to CRC cannot be excluded. Of note, as our manuscript was being finalized, this variant was reported in a 65‐year‐old patient with colorectal polyposis (57 adenomatous polyps), 48 and in a family with tooth agenesis and variable clinical findings including polyps and CRC, 49 and we recently identified another variant at the same position (c.1994del, p.(Gly665Alafs*24)) in a 66‐year‐old patient presenting with a similar phenotype (46 adenomatous polyps), suggesting once again that truncating variants in exon 8 are associated with colorectal polyposis and cancer susceptibility. Conversely, one missense AXIN2 variant (c.1387C>T, p.(Arg463Cys)) was reported in two siblings with attenuated adenomatous polyposis at young age 15 .…”

Section: Discussionmentioning

confidence: 95%

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AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer

Leclerc

Beaumont

Vibert³

et al. 2022

Genes Chromosomes & Cancer

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Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/ likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss-of-function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103-28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3-binding and DIX domains, but preserving the β-catenin-binding domain. Ninety-one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 95%

AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer

Leclerc

Beaumont

Vibert³

et al. 2022

Genes Chromosomes & Cancer

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“…For example, some institutional review boards in the US consider case studies or limited case series as not requiring research approval and half of the articles in this research were case studies or case series. The authors of one case study, conducted in Denmark, specifically noted that in an institutional review board approval was not necessary for their case report in a journal article (Jensen, et al, 2021). Another case report article (conducted in Australia) indicated that consent was provided verbally (Beard, et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

The Profile of Articles on AXIN2 Mutations, Oligodontia, and Ethical Statements in Dental Research

Wiener

2022

Journal of Empirical Research on Human Research Ethics

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Purpose Editors often require ethical statements in research publications. This is particularly important with genetic data where discrimination may occur upon data disclosures. The purpose of this research is to determine if there was a positive trend of publishing ethical statements in dental genetic research. The study is limited to AXIN2 mutations which may be associated with oligodontia and cancer. Methods A MEDLINE search of 2011–2021 articles concerning AXIN2, oligodontia, and ethical statements was conducted. Reviews, nonhuman subject research, abstracts, and articles not written nor translated into English were excluded. Results Forty-four studies were found; 10 excluded. There were 25 (75.8%) with ethical statements, and 25 (75.8%) with participant consent statements. There was no significant difference by year in ethical statements over the ten years (p = 0.094). Conclusion There is a need to encourage more ethical statements in publications especially for genetically sensitive topics to reassure readers of ethical practices.

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“…Heterozygosity for germline variants in AXIN2 and its relation to tooth anomalies, gastrointestinal polyps, and the risk of CRC was first described in 2004 [44]. One group diagnosed up to 100 colon polyps in carriers of AXIN2 variants from age 31 years [45]. Cases of germline variants in AXIN2 related to ectodermal dysplasia have been reported as well [46,47].…”

Section: Axin2-associated Oligodontia-colorectal Cancer Syndromementioning

confidence: 99%

Nonmalignant Features Associated with Inherited Colorectal Cancer Syndromes-Clues for Diagnosis

Haimov

Lieberman

Castellví–Bel

et al. 2022

Cancers

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Genetic diagnosis of affected individuals and predictive testing of their at-risk relatives, combined with intensive cancer surveillance, has an enormous cancer-preventive potential in these families. A lack of awareness may be part of the reason why the underlying germline cause remains unexplained in a large proportion of patients with CRC. Various extracolonic features, mainly dermatologic, ophthalmic, dental, endocrine, vascular, and reproductive manifestations occur in many of the cancer predisposition syndromes associated with CRC and polyposis. Some are mediated via the WNT, TGF-β, or mTOR pathways. However the pathogenesis of most features is still obscure. Here we review the extracolonic features of the main syndromes, the existing information regarding their prevalence, and the pathways involved in their pathogenesis. This knowledge could be useful for care managers from different professional disciplines, and used to raise awareness, enable diagnosis, and assist in the process of genetic testing and interpretation.

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Familial colorectal cancer and tooth agenesis caused by an AXIN2 variant: how do we detect families with rare cancer predisposition syndromes?

Cited by 7 publications

References 20 publications

AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer

AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer

The Profile of Articles on AXIN2 Mutations, Oligodontia, and Ethical Statements in Dental Research

Nonmalignant Features Associated with Inherited Colorectal Cancer Syndromes-Clues for Diagnosis

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