Genetic variants within the hTERT gene and the risk of colorectal cancer in Lynch syndrome.

Aung Ko Win,William Crawford,Ingrid M Winship,Graham G Giles,Mark A Jenkins,Christophe Rosty,Susan G Preston,Mark Clendenning,John L Hopper,Daniel D Buchanan,Susan Parry,Melissa C Southey,John A Baron,Finlay A Macrae

doi:10.18632/genesandcancer.85

Aung Ko Win, William Crawford + Show 12 more

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https://doi.org/10.18632/genesandcancer.85

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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.

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Lynch syndrome, formerly known as hereditary non-polyposis colorectal cancer, is an autosomal dominant disorder caused by germline mutations in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, or EPCAM
We examined whether single nucleotide polymorphisms (SNPs) within the hTERT gene act as genetic modifiers of colorectal cancer (CRC) risk for MMR gene mutation carriers
We found no evidence of association between any of the 23 SNPs within the hTERT gene and CRC risk either overall or when stratified by sex or specific MMR gene mutation, suggesting that hTERT SNPs do not modify the risk of CRC for MMR gene mutation carriers

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Formerly known as hereditary non-polyposis colorectal cancer, is an autosomal dominant disorder caused by germline mutations in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, or EPCAM. The hTERT gene (MIM 187270) encodes telomerase reverse transcriptase, the catalytic subunit of telomerase, an important protein for maintaining telomere length. Genetic variation within this gene has been shown to affect telomerase activity and telomere length and is thought to underlie an increased risk for cancer [6]. Genetic association studies in breast, ovarian, endometrial, lung, glioma, and pancreatic cancers have identified multiple single nucleotide polymorphisms (SNPs) in the hTERT gene that are associated with an increased risk of cancer [7]. We hypothesized that genetic variation within hTERT may act as a genetic modifier of CRC risk for MMR gene mutation carriers

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