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

Abstract

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.Electronic supplementary materialThe online version of this article (doi:10.1007/s10689-016-9934-0) contains supplementary material, which is available to authorized users.

Update on Hereditary Colorectal Cancer: Improving the Clinical Utility of Multigene Panel Testing

“…Germline point mutations and large deletions in the mothers against decapentaplegic homolog 4 (SMAD4) 44,131 and bone morphogenetic protein receptor type 1A (BMPR1A) 132 genes, underlie 40% to 60% of families with the JPS phenotype. 133 In addition, germline mutations in BMPR1A have been associated with a proportion of previously genetically unexplained familial or atypical adenomatous polyposis patients, 80 and a small proportion of patients meeting familial CRC type X (FCCTX) criteria, 134 thus expanding the phenotypic spectrum for this gene, and warranting its inclusion in multigene panels for CRC/polyposis testing. The diagnostic yield for patients with PJS and CS phenotypes is higher than JPS; up to 96% of individuals with PJS have an identified germline mutation in serine/threonine kinase 11 (STK11) 135,136 and approximately 80% of patients with CS have a mutation in the phosphatase and tensin homolog (PTEN) gene.…”

“…Multigene panel testing for CRC has an increased clinical yield over iterative single gene or phenotype driven testing and is cost-effective. 6 The yield of moderate-to-high penetrance mutations from CRC gene panel testing Hereditary CRC and the Utility of Multigene Panel Testing e300 -Clinical Colorectal Cancer June 2018 has been reported to be 10% to 18% in differing CRC and polyposis cohorts 4,80,[171][172][173] but is dependent on the genes included on the panel. Importantly, to facilitate effective and appropriate clinical care and counseling, robust estimates of CRC risk are pivotal.…”

Appropriate Management of Attenuated Familial Adenomatous Polyposis: Report of a Case and Review of the Literature

“…Data from Rohlin et al [22] confirmed overlapping phenotypes between different herditary CRC syndromes and the importance of using multigene panels. Authors applied a panel including 19 CRC susceptibility genes to 91 individuals of 6 phenotypic subgroups.…”

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

“…The mutational screening of MSH3 in our cohort did not identify any biallelic carriers. Two predicted deleterious variants were identified in heterozygosity in three unrelated patients: c.1394A>G (p.Y465C), located in the ATPase region of the MutS domain V (C‐terminal domain; Source: PFAM), and c.2732T>G (p.L911W) (Duraturo et al, ; Morak et al, ; Rohlin et al, ), affecting the MutS domain II (connector domain; Source: PFAM) and identified in two unrelated individuals (Table S1). Even if the two MSH3 variants are located in domains that play a critical role in MMR, their clinical significance is most probably inexistent in the absence of a second mutation in the other allele (Adam et al, ).…”