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©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases
Jun-Xiao Zhang, Lei Fu, Richarda M de Voer, Marc-Manuel Hahn, Peng Jin, Chen-Xi Lv, Eugène TP Verwiel, Marjolijn JL Ligtenberg, Nicoline Hoogerbrugge, Roland P Kuiper, Jian-Qiu Sheng, Ad Geurts van Kessel
Jun-Xiao Zhang, Richarda M de Voer, Marc-Manuel Hahn, Eugène TP Verwiel, Marjolijn JL Ligtenberg, Nicoline Hoogerbrugge, Roland P Kuiper, Ad Geurts van Kessel, Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands
Lei Fu, Peng Jin, Chen-Xi Lv, Jian-Qiu Sheng, Department of Gastroenterology, General Hospital of Beijing Military Region, Beijing 100700, China
Lei Fu, Third Military Medical University, Chongqing 400038, China
Marjolijn JL Ligtenberg, Department of Human Genetics and Department of Pathology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
Author contributions: Zhang JX, Fu L contributed equally to this paper; Zhang JX analyzed the data and performed the experiments; Fu L prepared the samples for exome sequencing, provided clinical information and performed validation experiments; de Voer RM, Hahn MM and Verwiel ET participated in the data analysis; Jin P participated in the sample collection; Lv CX performed the experiment for screening the control cohort; Ligtenberg MJ and Hoogerbrugge N participated in the design of the study; Kuiper RP, Sheng JQ and Geurts van Kessel A conceived and coordinated the study; Sheng JQ, de Voer RM, Kuiper RP and Geurts van Kessel A wrote the manuscript, which was approved by all co-authors.
Supported by research grants from the Dutch Cancer Society (KWF, KUN-4335), the Netherlands Organization for Scientific Research (NWO, 91710358), the Royal Dutch Academy of Sciences (KNAW), National Natural Science Foundation of China (NSFC, 81272194 and 81072041), and a scholarship from the China Scholarship Council (CSC) to Zhang JX.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Jian-Qiu Sheng, Professor, Department of Gastroenterology, General Hospital of Beijing Military Region, 5 Nanmenchang, Dongcheng, Beijing 100700, China. jianqiu@263.net
Telephone: +86-10-66721299 Fax: +86-10-66721299
Received: June 12, 2014
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
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.
