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Int J Cancer. 2020 Mar 15;146(6):1568-1577. doi: 10.1002/ijc.32683. Epub 2019 Nov 6.

Using linkage studies combined with whole-exome sequencing to identify novel candidate genes for familial colorectal cancer.

Author information

1
Neuroscience Research Australia, Sydney, Australia.
2
School of Medical Sciences, University of New South Wales, Sydney, Australia.
3
Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, University of Barcelona, Barcelona, Spain.
4
Pathology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) and Tumor Bank-Biobank, Hospital Clínic, Barcelona, Spain.
5
Gastroenterology Department, Hospital Donostia-Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Basque Country University (UPV/EHU), San Sebastian, Spain.
6
Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Sanitaria Galicia Sur, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Ourense, Spain.
7
Molecular Oncology Laboratory, Hospital Clinico San Carlos, CIBERONC (Centro de Investigacion Biomedica en Red de Cancer), IdISSC, Madrid, Spain.

Abstract

Colorectal cancer (CRC) is a complex disorder for which the majority of the underlying germline predisposition factors remain still unidentified. Here, we combined whole-exome sequencing (WES) and linkage analysis in families with multiple relatives affected by CRC to identify candidate genes harboring rare variants with potential high-penetrance effects. Forty-seven affected subjects from 18 extended CRC families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. Suggestive linkage peaks were identified on chromosomes 1q22-q24.2 (maxSNP = rs2134095; LODlinear = 2.38, LODexp = 2.196), 7q31.2-q34 (maxSNP = rs6953296; LODlinear = 2.197, LODexp = 2.149) and 10q21.2-q23.1 (maxSNP = rs1904589; LODlinear = 1.445, LODexp = 2.195). These linkage signals were replicated in 10 independent sets of random markers from each of these regions. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 89 rare variants predicted to be deleterious from 78 genes under the linkage intervals. This analysis showed significant segregation of rare variants with CRC in 18 genes (weighted p-value > 0.0028). Protein network analysis and functional evaluation were used to suggest a plausible candidate gene for germline CRC predisposition. Etiologic rare variants implicated in cancer germline predisposition may be identified by combining traditional linkage with WES data. This approach can be used with already available NGS data from families with several sequenced members to further identify candidate genes involved germline predisposition to disease. This approach resulted in one candidate gene associated with increased risk of CRC but needs evidence from further studies.

KEYWORDS:

colorectal cancer; genetic predisposition to disease; linkage analysis; whole-exome sequencing

PMID:
31525256
PMCID:
PMC7004061
DOI:
10.1002/ijc.32683
[Indexed for MEDLINE]
Free PMC Article

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