Published online Apr 14, 2015. doi: 10.3748/wjg.v21.i14.4136
Peer-review started: June 13, 2014
First decision: July 21, 2014
Revised: October 17, 2014
Accepted: December 1, 2014
Article in press: December 1, 2014
Published online: April 14, 2015
Processing time: 306 Days and 16.9 Hours
AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer (CRC) predisposing genes in early-onset or familial CRC cases.
METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with non-polyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 first-degree relative diagnosed with CRC at ≤ 55 years of age. Genomic DNA from blood was enriched for exome sequences using the SureSelect Human All Exon Kit, version 2 (Agilent Technologies) and sequencing was performed on an Illumina HiSeq 2000 platform. Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes.
RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing. In 6 of the 21 families (29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1 (5 patients), MSH2 (1 patient), and MUTYH (biallelic, 1 patient), five of which were reported as pathogenic. In the remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations. One previously unreported variant identified in a conserved region of EIF2AK4 (p.Glu738_Asp739insArgArg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy (33.3% vs 7%, P < 0.001).
CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.
Core tip: Mendelian colorectal cancer (CRC) predisposition syndromes underlie about 5% of all CRCs, and are caused by germline mutations in a limited set of genes. The overall heritability of CRC, however, is estimated to be approximately 30% and as yet many families at risk remain unexplained. This research identifies seven mutations of known CRC predisposing genes (MLH1, MSH2 and MUTYH) in 6 of the 21 families (29%), five of which were previously reported as pathogenic. One unreported variant EIF2AK4 (p.Glu738_Asp739insArgArg) located at conserved region was found to represent a local Chinese variant and significantly enriched in our early-onset CRC patient cohort.