title: Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Jun-Xiao
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Richarda M
authors.initials: RM
authors.lastname: de Voer
authors.affiliation: 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.
authors.forename: Marc-Manuel
authors.initials: MM
authors.lastname: Hahn
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Chen-Xi
authors.initials: CX
authors.lastname: Lv
authors.affiliation: 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.
authors.forename: Eugène Tp
authors.initials: ET
authors.lastname: Verwiel
authors.affiliation: 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.
authors.forename: Marjolijn Jl
authors.initials: MJ
authors.lastname: Ligtenberg
authors.affiliation: 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.
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.affiliation: 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.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.affiliation: 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.
authors.forename: Jian-Qiu
authors.initials: JQ
authors.lastname: Sheng
authors.affiliation: 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.
authors.forename: Ad
authors.initials: A
authors.lastname: Geurts van Kessel
mesh_terms: D000328:Adult; D017668:Age of Onset; D044466:Asian People / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D019295:Computational Biology; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D040941:Heredity; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012307:Risk Factors; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: Cancer predisposition; Colorectal cancer; Early-onset; Exome sequencing; Germline variants