Using linkage studies combined with whole‐exome sequencing to identify novel candidate genes for familial colorectal cancer. Issue 6 (6th November 2019)

• Record Type: Journal Article
• Authors: Toma, Claudio; Díaz‐Gay, Marcos; Franch‐Expósito, Sebastià; Arnau‐Collell, Coral; Overs, Bronwyn; Muñoz, Jenifer; Bonjoch, Laia; Soares de Lima, Yasmin; Ocaña, Teresa; Cuatrecasas, Miriam; Castells, Antoni; Bujanda, Luis; Balaguer, Francesc; Cubiella, Joaquín; Caldés, Trinidad; Fullerton, Janice M.; Castellví‐Bel, Sergi
• Is Part Of: International journal of cancer. Volume 146:Issue 6(2020)
• Page Start: 1568
• Page End: 1577
• Publication Date: 2019-11-06
• Subjects: colorectal cancer -- whole‐exome sequencing -- linkage analysis -- genetic predisposition to disease; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32683
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? Inherited genetic factors are thought to account for more than one‐third of colorectal cancer (CRC) cases. Most predisposing genetic factors, however, remain unidentified. Here, genome‐wide linkage analysis using whole‐exome sequencing (WES) data was performed in families with marked CRC aggregation. The combined linkage‐sequencing approach identified possible linkage peaks on chromosomes 1q22‐q24.2, 7q31.2‐q34, and 10q21.2‐q23.1. Analyses of potentially pathogenic variants revealed significant segregation of rare variants in 18 genes, while functional analyses identified a plausible candidate gene for germline CRC predisposition. The findings underscore the utility of linkage analysis employing WES for the discovery of candidate genes for disease predisposition.