title: Genetic variants within the hTERT gene and the risk of colorectal cancer in Lynch syndrome.
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 and 18 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.
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Crawford
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia; Envoi Specialist Pathologists, Herston, Queensland, Australia; University of Queensland, School of Medicine, Herston, Queensland, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Preston
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: New Zealand Familial Gastrointestinal Cancer Service, Auckland, New Zealand.
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia; Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia; Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Finlay A
authors.initials: FA
authors.lastname: Macrae
authors.affiliation: Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia; Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Winship
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
keywords: Lynch syndrome; colorectal cancer; genetic modifier; genetic variant; hTERT