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

Bellido, Fernando; Guinó, Elisabet; Jagmohan–Changur, Shantie; Seguí, Núria; Pineda, Marta; Navarro, Matilde; Lázaro, Conxi; Blanco, Ignacio; Vasen, Hans F. A.; Capellà, Gabriel; Wijnen, Juul T.; Valle, Laura

doi:10.1038/ejhg.2012.204

Cited by 20 publications

(19 citation statements)

References 44 publications

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“…A recent study of 930 MMR gene mutation carriers reported no overall difference in genotype frequencies between carriers affected and unaffected with CRC for the rs2075786 SNP in hTERT (RR=2.46; 95% CI=0.78–7.82) [ 10 ], a finding that is consistent with ours. This study also reported marginally significant evidence of association between the AA genotype of the rs2075786 SNP and cancer risk for carriers diagnosed with Lynch syndrome related-cancer diagnosed before the age of 45 years (RR=2.90; 95% CI=1.02–8.26; p=0.05) but we found no evidence of an association for that SNP and CRC risk before age 45 years.…”

Section: Discussionsupporting

confidence: 89%

“…Using data from the International HapMap project ( http://www.HapMap.org ) and Haploview program (version 3.12) and a minimum r 2 threshold of 0.8 we identified a set of tagging SNPs to capture the genetic variation in the hTERT gene. SNPs previously associated with CRC risk [ 8 , 9 , 17 ] or from the single study of CRC risk in MMR gene mutation carriers [ 10 ] were also genotyped. The selected SNPs ( Supplementary Table 1 ) were genotyped using Sequenom's iPLEX Gold.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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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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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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“…a risk modifier. This is supported by our recent observation that a variant in the telomerase gene, hTERT , increases cancer risk in young LS patients (<45 years of age), as it is associated with shortened telomeres in cancer-affected MMR gene mutation carriers [11]. Further studies assessing telomere length before and after cancer diagnosis in CRC patients will provide a definitive answer regarding the suggested effect of cancer on telomere length in blood cells.…”

Section: Discussionmentioning

confidence: 57%

“…Moreover, we have recently shown that a common genetic variant located in the telomerase gene ( hTERT ; MIM 187270) increases cancer risk in LS patients at early ages, and that this SNP is associated with shortened telomere length in cancer-affected MMR gene mutation carriers [11]. Telomeres consist of multiple short repeats (TTTAGG) at the ends of chromosomes and protect them against large-scale genomic rearrangements.…”

Section: Introductionmentioning

confidence: 99%

Telomere Length and Genetic Anticipation in Lynch Syndrome

et al. 2013

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Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.

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“…61–63 Recent associations have also been made between genes regulating the cell cycle, xenobiotic-metabolizing enzymes, and telomerase and young age of CRC onset in MMR gene mutation carriers. 64–66 …”

Section: Clinical Features and Cancer Risks In Lynch Syndromementioning

confidence: 99%

History, Genetics, and Strategies for Cancer Prevention in Lynch Syndrome

Kastrinos

Stoffel

2014

Clinical Gastroenterology and Hepatology

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Colorectal cancer (CRC) is the most common gastrointestinal malignancy and the third cause of cancer death in men and women in the United States. The majority of CRC cases diagnosed annually are due to sporadic events, but up to 6% are attributed to known monogenic disorders that confer a markedly increased risk for the development of CRC and multiple extracolonic malignancies. Lynch syndrome is the most common inherited CRC syndrome and is associated with mutations in DNA mismatch repair genes, mainly MLH1 and MSH2 but also MSH6, PMS2, and EPCAM. Although the risk of CRC and endometrial cancer may approach near 75% and 50%, respectively, in gene mutation carriers, the identification of these individuals and at-risk family members through predictive genetic testing provides opportunities for cancer prevention including specialized cancer screening, intensified surveillance, and/or prophylactic surgeries. This article will provide a review of the major advances in risk assessment, molecular genetics, DNA mutational analyses, and cancer prevention and management made since Lynch syndrome was first described 100 years ago.

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

Cited by 20 publications

References 44 publications

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

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

Telomere Length and Genetic Anticipation in Lynch Syndrome

History, Genetics, and Strategies for Cancer Prevention in Lynch Syndrome

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