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.
Highlights
Lynch syndrome (LS) (MIM 120435) is an autosomal-dominant inherited disorder caused by germline mutations in the DNA mismatch repair (MMR) genes
Spanish study No differences in rs2075786 genotype distributions were observed when comparing MMR gene mutation carriers affected with cancer, either LS-related or only colorectal cancer (CRC), and unaffected mutation carriers (Supplementary Table S1)
Differences did not reach significance and larger series should be studied to draw definitive conclusions, the results suggest that the effect of rs2075786 on cancer risk occurs for both MLH1 and MSH2 mutation carriers under the age of 45 (RRMLH1o45_AA 1⁄4 3.86; 95% confidence interval (CI) 1⁄4 0.70–21.33 and RRMSH2o45_AA 1⁄4 2.36; 95% CI 1⁄4 0.42–13.39)
Summary
Lynch syndrome (LS) (MIM 120435) is an autosomal-dominant inherited disorder caused by germline mutations in the DNA mismatch repair (MMR) genes. There is a considerable variation in LS expression and no obvious gene-specific genotype/phenotype correlations have been demonstrated nor does there appear to be any relationship between the location of a mutation and type of disease. In addition to environmental factors, there is evidence suggesting the existence of genetic factors that somehow explain the variability in individual cancer risk.[10] Identifying the genetic modifiers of risk can lead to an efficient stratification of mutation carriers based on their predicted risk, implying a more appropriate clinical management based on personalized surveillance programs
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