GREM1 and POLE variants in hereditary colorectal cancer syndromes

Abstract

Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high‐penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy‐number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease‐causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease‐causing mutations in hereditary CRC syndromes. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

Genotyping of colorectal cancer for cancer precision medicine: Results from the IPH Center for Molecular Pathology

“…To elucidate this issue further, we performed Sanger sequencing of tumor and matched normal tissue of three randomly selected cases harboring 4 NAV in total. While three of the NAV affecting SMAD4 , SOX9 , and TGFRB2 , respectively, were of somatic origin, the fourth NAV turned out to be an apparently rare germline SNP of POLE that was only very recently described in an individual with colorectal cancer (Rohlin et al, ).…”

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017

“…33 Exome sequencing combined with linkage analyses and detection of copy-number variations identified a 16-kb duplication upstream of GREM1 in a family of non-Ashkenazi Jewish descent with AFAP. 35 For carriers of GREM1 alterations, the panel recommends similar management strategies as described for carriers of AXIN2 mutations (see GENE-7; page 1470).…”

Identification of a novel GREM1 duplication in a patient with multiple colon polyps

“…Both the 40kb [3] and 16kb duplications [4] have been shown to significantly increase GREM1 expression. While the 57kb [5] and this novel 24kb duplication completely overlap the GREM1 enhancer region and support the clinical phenotype, the impact upon expression level resulting from these duplications has not been assessed explicitly.…”

“…Subsequently, two additional GREM1 duplications have been reported: a 16kb duplication in the regulatory region of GREM1 was identified in a non-Ashkenazi Jewish family with attenuated polyposis [4] and a 57kb duplication of the entire GREM1 gene was identified in an individual with early onset colon cancer [5]. Given the association of GREM1 with HMPS, analysis of the GREM1 5′ regulatory region is now available and included in many hereditary cancer gene panels offered by commercial genetic testing laboratories.…”