Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

Abstract

Technological advances have allowed the identification of new adenomatous and serrated polyposis genes, and of several candidate genes that require additional supporting evidence of causality. Through an exhaustive literature review and mutational screening of 177 unrelated polyposis patients, we assessed the involvement of MCM9, FOCAD, POLQ, and RNF43 in the predisposition to (nonserrated) colonic polyposis, as well as the prevalence of NTHL1 and MSH3 mutations among genetically unexplained polyposis patients. Our results, together with previously reported data and mutation frequency in controls, indicate that: MCM9 and POLQ mutations are not associated with polyposis; germline RNF43 mutations, with a prevalence of 1.5–2.5% among serrated polyposis patients, do not cause nonserrated polyposis; MSH3 biallelic mutations are highly infrequent among European polyposis patients, and the prevalence of NTHL1 biallelic mutations among unexplained polyposes is ~2%. Although nonsignificant, FOCAD predicted deleterious variants are overrepresented in polyposis patients compared to controls, warranting larger studies to provide definite evidence in favor or against their causal association with polyposis predisposition.

Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review

“…(e) Our analysis was mostly restricted to nonpolyposis CRC, while some genes, such as MCM9 or POLQ , might exert their effect in a polyposis context. This issue has been recently addressed by our group (Terradas et al, 2019). (f) Comparisons between cases and controls were mainly performed on gene basis and not per variant, except for those variants with higher allele frequencies (e.g.…”

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

“…Homozygous variants in MCM9 , a DNA helicase involved in HR, DNA replication and MMR, were described in two polyposis-affected siblings [ 57 ]. However, recent case-control data suggests a lack of association of homozygous or heterozygous variants with polyposis or CRC predisposition [ 10 , 58 ]. A frameshift mutation in XRCC4 , a member of the DNA ligase 4 complex involved in the last step of NHEJ, was found in a CRC patient with familial CRC history, which, together with the lack of XRCC4 variant carriers among population controls, led the authors to propose XRCC4 as a candidate gene for CRC predisposition [ 13 ].…”

Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium

“…Hence, prevalence of NTHL1 biallelic carriers among French probands suspected of predisposition to colorectal cancer and polyposis is of 0.2% (8/3936 index cases). As a 1.9% prevalence was estimated among unexplained polyposis patients (5/263 index cases with polyposis), 2 numbers for colorectal cancers and polyposis may not be comparable. Polyposis seems a more specific criterion, but we were unable to define a polyposis series among the 3936 patients with colorectal cancer and/or polyposis patients.…”

“…This syndrome was firstly described in 2015 from whole exome analyses (WES) in a series of polyposis patients without pathogenic variant identified in the APC or MUTYH genes which led to identification of seven homozygous carriers of the NTHL1 c.268C>T p.(Gln90*) (NM_002528.6) truncating variant (rs150766139) 1 . To date, a 1.9% prevalence of NTHL1 pathogenic variants among unexplained polyposis patients has been described (5/263 polyposis families) 2 and only 36 biallelic NTHL1 variant carriers from 23 families have been reported 1‐11 . This syndrome seems to be close to the polyposis predisposition syndrome linked to MUTYH alterations, as it is characterized by colorectal cancers and attenuated adenomatous polyposis.…”

“…This syndrome seems to be close to the polyposis predisposition syndrome linked to MUTYH alterations, as it is characterized by colorectal cancers and attenuated adenomatous polyposis. Thus, adenomatous polyps have been demonstrated in all biallelic NTHL1 variant carriers who have undergone colonoscopy, associated, in some cases, with hyperplastic polyps 2 . Interestingly, half of the biallelic carriers also displayed multiple colonic or extra‐colonic primary tumors affecting mainly breast, endometrium, urothelium and brain 1‐10 …”