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Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome.

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.

SUBMITTER: Bellido F

PROVIDER: S-EPMC3641380 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome.

Bellido Fernando F Guinó Elisabet E Jagmohan-Changur Shantie S Seguí Nuria N Pineda Marta M Navarro Matilde M Lázaro Conxi C Blanco Ignacio I Vasen Hans F A HF Moreno Victor V Capellá Gabriel G Wijnen Juul T JT Valle Laura L

European journal of human genetics : EJHG 20120905 5

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 ...[more]

PMID: 22948024

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Project description:Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair (MMR) genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer; however, the risk of pancreatic cancer in Lynch syndrome is uncertain and not quantified.To estimate pancreatic cancer risk in families with germline MMR gene mutations.Cancer histories of probands and their relatives were evaluated in MMR gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute (n = 80), Boston, Massachusetts, and University of Michigan Comprehensive Cancer Center (n = 67), Ann Arbor, Michigan. Families enrolled before the study start date (June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared with the general population using modified segregation analysis, with correction for ascertainment.Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk.Data on 6342 individuals from 147 families with MMR gene mutations were analyzed. Thirty-one families (21.1%) reported at least 1 case of pancreatic cancer. Forty-seven pancreatic cancers were reported (21 men and 26 women), with no sex-related difference in age of diagnosis (51.5 vs 56.5 years for men and women, respectively). The cumulative risk of pancreatic cancer in these families with gene mutations was 1.31% (95% confidence interval [CI], 0.31%-2.32%) up to age 50 years and 3.68% (95% CI, 1.45%-5.88%) up to age 70 years, which represents an 8.6-fold increase (95% CI, 4.7-15.7) compared with the general population.Among 147 families with germline MMR gene mutations, the risk of pancreatic cancer was increased compared with the US population. Individuals with MMR gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of premalignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance.

Project description:IntroductionLynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in the DNA mismatch repair (MMR) genes. Mutation carriers have a substantial burden of increased risks of cancers of the colon, rectum, endometrium and several other organs which generally occur at younger ages than for the general population. The issue of whether breast cancer risk is increased for MMR gene mutation carriers has been debated with evidence for and against this association.MethodsUsing the PUBMED, we identified all relevant studies of breast cancer associated with Lynch syndrome that were published by 15 December 2012. In the review, we included: (i) molecular studies that reported microsatellite instability and/or immunohistochemistry in breast cancer tumors of MMR gene mutation carriers; and (ii) risk studies that investigated risk of breast cancer for confirmed MMR gene mutation carriers or families or clinically and/or pathologically defined Lynch syndrome families.ResultsWe identified 15 molecular studies and, when combined, observed 62 of 122 (51%; 95% CI 42 to 60%) breast cancers in MMR gene mutation carriers were MMR-deficient. Of the 21 risk studies identified, 13 did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome while 8 studies found an increased risk of breast cancer ranging from 2- to 18-fold compared with the general population (or non-carriers). There is only one prospective study demonstrating an elevated risk of breast cancer for MMR gene mutation carriers compared with the general population (standardized incidence ratio 3.95; 95% CI 1.59, 8.13).ConclusionsSince breast cancer is a relatively common disease in the general population, more precise estimates of risk and gene-specific risks will need to utilize large prospective cohort studies with a long follow-up. While current data are inconclusive at a population level, individual tumor testing results suggest that MMR deficiency is involved with breast cancers in some individuals with Lynch syndrome.

Dataset Information

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome.

Publications

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome.

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