These authors contributed equally to this work.
Exome Resequencing Identifies Potential Tumor-Suppressor Genes that Predispose to Colorectal Cancer
Article first published online: 20 MAY 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 7, pages 1026–1034, July 2013
How to Cite
Smith, C. G., Naven, M., Harris, R., Colley, J., West, H., Li, N., Liu, Y., Adams, R., Maughan, T. S., Nichols, L., Kaplan, R., Wagner, M. J., McLeod, H. L. and Cheadle, J. P. (2013), Exome Resequencing Identifies Potential Tumor-Suppressor Genes that Predispose to Colorectal Cancer. Hum. Mutat., 34: 1026–1034. doi: 10.1002/humu.22333
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.
- Issue published online: 18 JUN 2013
- Article first published online: 20 MAY 2013
- Accepted manuscript online: 13 APR 2013 09:00AM EST
- Manuscript Accepted: 26 MAR 2013
- Manuscript Received: 16 AUG 2012
- Kidani Trust
- Cancer Research Wales
- Cardiff CRUK Centre
- Wales Assembly Government NISCHR Cancer Genetics BRU
- Wales Gene Park, NIH. Grant Number: UL1 RR025747
- University of North Carolina University Cancer Research Fund
- Wellcome Trust. Grant Number: 076113/C/04/Z
- Juvenile Diabetes Research Foundation. Grant Number: WT061858
- National Institute of Health Research of England
- colorectal cancer;
- exome resequencing;
- tumor suppressor
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.