GREM1 and POLE variants in hereditary colorectal cancer syndromes
Journal article, 2016

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.


Anna Rohlin

University of Gothenburg

Frida Eiengård

University of Gothenburg

Ulf Lundstam

University of Gothenburg

Theofanis Zagoras

University of Gothenburg

Staffan Nilsson

University of Gothenburg

Chalmers, Mathematical Sciences, Mathematical Statistics

Anders Edsjö

University of Gothenburg

Jan Pedersen

Rikshospitalet-Radiumhospitalet HF

Janhenry Svensson

Skaraborg Hospital

Stefan Skullman

Skaraborg Hospital

B Göran Karlsson

University of Gothenburg

Jan Björk

Karolinska Institutet

Margareta Nordling

University of Gothenburg

Genes Chromosomes and Cancer

1045-2257 (ISSN) 1098-2264 (eISSN)

Vol. 55 1 95-106

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