Abstract
Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative riskLSca<45_AA=2.90; 95% confidence interval=1.02–8.26). Rs2075786 is associated with colorectal cancer (CRC) risk neither in the general population nor in non-Lynch CRC families. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, retinoid X receptor alpha, probably causing early telomerase activation and therefore accelerated carcinogenesis. Notably, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In conclusion, MMR gene mutation carriers with hTERT rs2075786 are at high risk to develop a LS-related tumor at an early age. Cancer-preventive measures and stricter cancer surveillance at early ages might help prevent or early detect cancer in these mutation carriers.
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Acknowledgements
We thank all the people responsible for genetic counseling and genetic testing in hereditary cancer at both Catalan Institute of Oncology and Leiden University Medical Center, and Gemma Aiza for technical support. This work was partly funded by the Spanish Ministry of Science and Innovation (grant BFU2009-10281 and Ramón y Cajal contract, both to LV; and fellowship to FB), the Scientific Foundation of Asociación Española Contra el Cáncer, the Carlos III Health Institute (ISCIIIRETIC: RD06/0020/1051 and RD06/0020/1050; FIS PI08/1635, FIS PI08/1359 and FIS PS09-01037; and fellowship to NS), the Catalan Health Institute and the Autonomous Government of Catalonia (2009SGR290, 2009SGR1489), and CIBERESP (CB07/02/2005).
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Bellido, F., Guinó, E., Jagmohan-Changur, S. et al. Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome. Eur J Hum Genet 21, 511–516 (2013). https://doi.org/10.1038/ejhg.2012.204
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DOI: https://doi.org/10.1038/ejhg.2012.204
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