GREM1 and POLE variants in hereditary colorectal cancer syndromes
Artikel i vetenskaplig tidskrift, 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

Göteborgs universitet

Frida Eiengård

Göteborgs universitet

Ulf Lundstam

Göteborgs universitet

Theofanis Zagoras

Göteborgs universitet

Staffan Nilsson

Chalmers, Matematiska vetenskaper, Matematisk statistik

Göteborgs universitet

Anders Edsjö

Göteborgs universitet

Jan Pedersen

Rikshospitalet-Radiumhospitalet HF

Janhenry Svensson

Skaraborgs Sjukhus

Stefan Skullman

Skaraborgs Sjukhus

B Göran Karlsson

Göteborgs universitet

Jan Björk

Karolinska Institutet

Margareta Nordling

Göteborgs universitet

Genes Chromosomes and Cancer

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

Vol. 55 1 95-106







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