Genetic variants within the hTERT gene and the risk of colorectal cancer in Lynch syndrome
Aung Ko Win1, Mark Clendenning2, William Crawford2, Christophe Rosty2,3,4, Susan G. Preston2, Melissa C. Southey5, Susan Parry6, Graham G. Giles1,7, Finlay A. Macrae8,9,10, Ingrid M. Winship8,9, John A. Baron11, John L. Hopper1,12, Mark A. Jenkins1, Daniel D. Buchanan1,2
1 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
2 Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
3 Envoi Specialist Pathologists, Herston, Queensland, Australia
4 University of Queensland, School of Medicine, Herston, Queensland, Australia
5 Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
6 New Zealand Familial Gastrointestinal Cancer Service, Auckland, New Zealand
7 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia
8 Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
9 Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia
10 Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Victoria, Australia
11 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
12 Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea
Correspondence:
Daniel Buchanan, email:
Keywords: Lynch syndrome, hTERT, colorectal cancer; genetic modifier, genetic variant
Received: September 09, 2015 Accepted: November 01, 2015 Published: November 03, 2015
Abstract
Lynch syndrome is an inherited cancer-predisposing disorder caused by germline mutations in the DNA mismatch repair (MMR) genes but there is a high degree of variability in cancer risk observed among carriers, suggesting the existence of modifying factors. Our aim was to investigate variants within the hTERT gene as a potential colorectal cancer (CRC) risk modifier for MMR gene mutation carriers. We identified 1098 MMR gene mutation carriers (420 MLH1, 481 MSH2, 126 MSH6, 53 PMS2 and18 EPCAM) from 330 families recruited from either family cancer clinics or population cancer registries of the Australasian Colorectal Cancer Family Registry between 1997 and 2012. Using weighted Cox regression after adjusting for ascertainment bias, we estimated associations between 23 SNPs within the hTERT gene and CRC risk. During 46,836 person-years observation, 392 (36%) carriers were diagnosed with CRC at a mean age of 42.2 (standard deviation 11.4) years. There was no evidence of association between any of the hTERT SNPs and CRC risk, overall and stratified by sex and MMR gene mutated, after adjustment for multiple testing. Our findings suggest no evidence for clinical utility of the SNPs within the hTERT gene in Lynch syndrome.
