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Exome Resequencing Identifies Potential Tumor-Suppressor Genes that Predispose to Colorectal Cancer

Authors


  • Communicated by Georgia Chenevix-Trench

  • Contract grant sponsors: Tenovus; the Kidani Trust; Cancer Research Wales; the Cardiff CRUK Centre; the Wales Assembly Government NISCHR Cancer Genetics BRU; the Wales Gene Park, NIH (UL1 RR025747); the University of North Carolina University Cancer Research Fund; Wellcome Trust (Grant 076113/C/04/Z); the Juvenile Diabetes Research Foundation (Grant WT061858); the National Institute of Health Research of England.

ABSTRACT

Inherited factors account for around one third of all colorectal cancers (CRCs) and include rare high penetrance mutations in APC, MSH2, MSH6, and POLE. Here, we sought novel tumor-suppressor genes that predispose to CRC by exome resequencing 50 sporadic patients with advanced CRC (18 diagnosed ≤35 years of age) at a mean coverage of 30×. To help identify potentially pathogenic alleles, we initially sought rare or novel germline truncating mutations in 1,138 genes that were likely to play a role in colorectal tumorigenesis. In total, 32 such mutations were identified and confirmed, and included an insertion in APC and a deletion in POLE, thereby validating our approach for identifying disease alleles. We sought somatic mutations in the corresponding genes in the CRCs of the patients harboring the germline lesions and found biallelic inactivation of FANCM, LAMB4, PTCHD3, LAMC3, and TREX2, potentially implicating these genes as tumor suppressors. We also identified a patient who carried a germline truncating mutation in NOTCH3, part of the Notch signaling cascade that maintains intestinal homeostasis. Our whole exome analyses provided further gene lists to facilitate the identification of potential predisposition alleles.

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