N55: A Genetic Variant In Telomerase Gene Modifies Cancer Risk In Lynch Syndrome Patients Harbouring MSH2 Mutations

B. A. Talseth-Palmer1, 2, 3, T. J. Evans3, S.Belhadj4, K. A. Bolton3, S. Jagmohan-Changur5, J. T. Wijnen5, 6, H. F.A Vasen7, L. Valle Velasco4, R. J. Scott3, 8

1 – Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway. 2 – Research and Development Unit, Møre og Romsdal Hospital Trust, Molde, Norway. 3 – School of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia. 4 – Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Hospitalet de Llobregat, Barcelona, Spain. 5 – Deparment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 6 -Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 7 – Department of Gastroenterology and Hepatology,  Leiden University Medical Center, Leiden, The Netherlands. 8 – Pathology North, Hunter New England Health, Newcastle, NSW, Australia.

 

Aim: In this study chosen to genotype 3 SNPs in telomerase reverse transcriptase (TERT), as common genetic variants of the TERT gene are influencing telomere length and have been associated with a wide range of cancers, including colorectal cancer and Lynch syndrome (LS).

Method: We genotyped 1895 LS patients samples for rs2075786 (G>A) and 1241 LS patient samples for rs2736108 (C>T) and rs7705526 (C>A). Risk of LS cancer with each SNPs genotype was estimated using simple- and mixed-effects logistic regression adjusting for gene, gender and country of origin.

Results: We see an increased risk of LS cancers for patients carrying MSH2 mutations and heterozygous genotype (GA) for rs2075786 (OR=1.84, confidence interval (CI) =1.15-2.94), p=0.01). This association is even stronger if we divide the group into LS cancer <45 years of age at diagnosis and compare it to LS cancer free patients ((MSH2 and AA genotype) OR=2.53, CI=1.43-4.49, p=0.002).

Conclusion: Both MLH1 and MSH2 mutation carrier’s starts off with the same risk of cancer, but a SNP in TERT is associated with a differential risk of developing cancer for MSH2 mutation carriers. By including modifier gene/loci in risk algorithms it should be possible to tailor surveillance options for individual patients, allowing for better disease outcome.

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