GREM1 and POLE variants in hereditary colorectal cancer syndromes.
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.
Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
Anna
A
Rohlin
Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
Frida
F
Eiengård
Department of Surgery, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
Ulf
U
Lundstam
Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
Theofanis
T
Zagoras
Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
Staffan
S
Nilsson
Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.|Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Anders
A
Edsjö
Department of Medical Genetics, Rikshospitalet, University Hospital, Oslo, Norway.
Jan
J
Pedersen
Department of Surgery, Skaraborg Hospital, Skövde, Sweden.
Janhenry
J
Svensson
Department of Surgery, Skaraborg Hospital, Skövde, Sweden.
Stefan
S
Skullman
The Swedish NMR-Centre at University of Gothenburg, Gothenburg, Sweden.
B Göran
BG
Karlsson
Department of Medicine, The Swedish Polyposis Registry, Karolinska Institute, Stockholm, Sweden.
Jan
J
Björk
Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
Margareta
M
Nordling
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D004257:DNA Polymerase II / Q000737:chemistry / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008040:Genetic Linkage; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D010375:Pedigree; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D056916:Segmental Duplications, Genomic; D017422:Sequence Analysis, DNA
C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human