Hereditary Colorectal Cancer and Polyposis Syndromes Caused by Variants in Uncommon Genes.

A substantial number of hereditary colorectal cancer (CRC) and colonic polyposis cannot be explained by alteration in confirmed predisposition genes, such as mismatch repair (MMR) genes, APC and MUTYH. Recently, a certain number of potential predisposition genes have been suggested, involving each a small number of cases reported so far. Here, we describe the detection of rare variants in the NTLH1, AXIN2, RNF43, BUB1, and TP53 genes in nine unrelated patients who were suspected for inherited CRC and/or colonic polyposis. Seven of them were classified as pathogenic or likely pathogenic variants (PV/LPV). Clinical manifestations of carriers were largely consistent with reported cases with, nevertheless, distinct characteristics. PV/LPV in these uncommon gene can be responsible for up to 2.7% of inherited CRC or colonic polyposis syndromes. Our findings provide supporting evidence for the role of these genes in cancer predisposition, and contribute to the determination of related cancer spectrum and cancer risk for carriers, allowing for the establishment of appropriate screening strategy and genetic counseling in affected families.

Bouras A ，Fabre A ，Zattara H ，Handallou S ，Desseigne F ，Kientz C ，Prieur F ，Peysselon M ，Legrand C ，Calavas L ，Saurin JC ，Wang Q ... -  《-》

Update on genetic predisposition to colorectal cancer and polyposis.

The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.

Valle L ，de Voer RM ，Goldberg Y ，Sjursen W ，Försti A ，Ruiz-Ponte C ，Caldés T ，Garré P ，Olsen MF ，Nordling M ，Castellvi-Bel S ，Hemminki K ... -  《-》

Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing.

Rohlin A ，Rambech E ，Kvist A ，Törngren T ，Eiengård F ，Lundstam U ，Zagoras T ，Gebre-Medhin S ，Borg Å ，Björk J ，Nilbert M ，Nordling M ... -  《-》

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

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.

Leclerc J ，Beaumont M ，Vibert R ，Pinson S ，Vermaut C ，Flament C ，Lovecchio T ，Delattre L ，Demay C ，Coulet F ，Guillerm E ，Hamzaoui N ，Benusiglio PR ，Brahimi A ，Cornelis F ，Delhomelle H ，Fert-Ferrer S ，Fournier BPJ ，Hovnanian A ，Legrand C ，Lortholary A ，Malka D ，Petit F ，Saurin JC ，Lejeune S ，Colas C ，Buisine MP ... -  《-》

Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis.

Lejeune S ，Guillemot F ，Triboulet JP ，Cattan S ，Mouton C ，PAFNORD Group ，Porchet N ，Manouvrier S ，Buisine MP ... -  《-》