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Genet Med. 2015 Feb;17(2):131-42. doi: 10.1038/gim.2014.89. Epub 2014 Jul 24.

Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer.

Author information

1
Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
2
Plataforma de Bioinformática, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
3
Molecular Oncology Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
4
1] Centre Nacional d'Anàlisi Genòmica, Parc Científic de Barcelona, Barcelona, Spain [2] Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
5
Centre Nacional d'Anàlisi Genòmica, Parc Científic de Barcelona, Barcelona, Spain.
6
Department of Pathology, Hospital Clinic, Barcelona, Spain.
7
Galician Public Foundation of Genomic Medicine, Centro de Investigación Biomédica en Red de Enfermedades Raras, Genomics Medicine Group, Hospital Clínico, University of Santiago de Compostela, Galicia, Spain.
8
Department of Gastroenterology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Centre), Pompeu Fabra University, Barcelona, Spain.
9
Gastroenterology Department, Hospital Donostia - Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Country University (UPV/EHU), San Sebastián, Spain.

Erratum in

  • Genet Med. 2014 Dec;16(12):988-9.

Abstract

PURPOSE:

Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases.

METHODS:

Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0-0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen.

RESULTS:

Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1.

CONCLUSION:

We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.

PMID:
25058500
PMCID:
PMC4318970
DOI:
10.1038/gim.2014.89
[Indexed for MEDLINE]
Free PMC Article

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