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

Abstract

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.

Keywords: Wnt signaling pathway; adenomatous polyposis; colorectal cancer susceptibility; oligodontia.

FIGURE 1

Flowchart indicating the origins of the 11 pathogenic/likely pathogenic (P/LP) AXIN2 variants identified in French Oncogenetics laboratories. ^†Panel including APC, MUTYH, MLH1, MSH2, MSH6, PMS2, POLE, POLD1, SMAD4, BMPR1A, STK11, PTEN +/‐ NTHL1, GREM1/SCG5, and MSH3. ^‡One individual (Re‐3) with AFAP and CRC with co‐occurrence of a P/LP AXIN2 variant and a homozygous pathogenic MUTYH variant.

FIGURE 2

Genomic structure of AXIN2 gene showing the location of variants associated to colorectal adenomatous polyposis or CRC. Boxes represent exons. Pathogenic/likely pathogenic AXIN2 variants described in this study are indicated in black. All were novel, except two (marked by #)., Variants which were described in other studies are indicated in gray., , , , , Functional domains of AXIN2 protein are shown below., , , TBM, tankyrase‐binding motifs (role in regulation of AXIN2 stability);, , , RGS, regulator of G‐protein signaling (APC‐binding domain); GSK‐bd, glycogen synthase kinase 3β‐binding domain; β‐cat‐bd, β‐catenin‐binding domain; SMAD3‐bd, SMAD3‐binding domain;, DIX, Disheveled and Axin (Disheveled‐binding domain and Axin homodimerisation).

FIGURE 3

Pedigrees of patients with germline P/LP AXIN2 variants. Filled symbols, affected; +, variant carrier; −, non‐carrier; arrow, index case. Ages at diagnosis or at information gathering (in brackets) or at death (d.) are indicated. For colorectal polyps, the cumulative number from age at first presentation or screening colonoscopy to age at last contact is indicated. AOd, anodontia; AC, ampullary cancer; ad, adenoma; AdP, adenomatous polyposis; BC, breast cancer; CUP, cancer of unknown primary; CRC, colorectal cancer; EDy, ectodermal dysplasia; HNC, head and neck cancer; hp, hyperplastic polyps; IC, intestinal cancer (site not specified); IM, idiopathic myopathy; Lk, leukemia; Me, melanoma; OC, ovarian cancer; Od, oligodontia; PC, prostate cancer; SBC, small bowel cancer; Sbi, spina bifida; SGC, salivary gland cancer; ssa, sessile serrated adenoma; TC, thyroid cancer.

FIGURE 4

Panoramic radiograph of patient Li‐2 III.1. This radiograph shows oligodontia with absence of 12 permanent teeth (4 incisors [2 maxillary lateral and 2 mandibular central], 1 first molar, 3 second molars, and the 4 third molars). White stars indicate missing permanent teeth.