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GREM1 and POLE variants in hereditary colorectal cancer syndromes

Journal article
Authors Anna Rohlin
Frida Eiengård
Ulf Lundstam
Theofanis Zagoras
Staffan Nilsson
Anders Edsjö
Jan Pedersen
Janhenry Svensson
Stefan Skullman
B Göran Karlsson
Jan Björk
Margareta Nordling
Published in Genes, Chromosomes and Cancer
Volume 55
Issue 1
Pages 95–106
ISSN 1045-2257
Publication year 2016
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Clinical Sciences, Department of Surgery
Institute of Biomedicine, Department of Pathology
Department of Mathematical Sciences, Mathematical Statistics
Swedish NMR Centre at Göteborg University
Pages 95–106
Language en
Links dx.doi.org/10.1002/gcc.22314
Subject categories Surgery

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.

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