Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of... Show moreIndividuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p=0.0160). Kaplan-Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p=0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients. Show less
Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high... Show moreFamilial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with < 100 colorectal adenomas versus patients with aeyen100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the aeyen100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP. Show less
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... Show moreLynch 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. Show less
Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of... Show moreTwo colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data-sets was performed to better define this association. This cohort-study includes three sample populations combined totaling 1,352 individuals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR = 2.68, p ≤ 0.0001) increasing risk of CRC, and rs3802842 in a pair-wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log-rank test; p ≤ 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in individuals carrying three risk alleles compared to those with 0 risk alleles for the pair-wise SNP combination. A trend (due to significance threshold of p ≤ 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair-wise combination (p = 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program. Show less
Bellido, F.; Guino, E.; Jagmohan-Changur, S.; Segui, N.; Pineda, M.; Navarro, M.; ... ; Valle, L. 2012
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... Show moreLynch 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 risk(LSca<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.European Journal of Human Genetics advance online publication, 5 September 2012; doi:10.1038/ejhg.2012.204. Show less
