Abstract
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 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.
Highlights
Lynch syndrome (LS) is an autosomal dominantly inherited cancer syndrome that accounts for 2–5% of all colon cancer cases and approximately 2% of all endometrial cancer (EC) cases
Samples from the Netherlands and Spain were originally only genotyped for rs207578629, while the Australian and Polish were genotyped for this single nucleotide polymorphisms (SNPs) for the purpose of the current study
We present results from a large sample cohort of 1881 LS patients that statistically show that a polymorphism in telomerase reverse transcriptase (TERT) influences disease risk in LS patients
Summary
Lynch syndrome (LS) is an autosomal dominantly inherited cancer syndrome that accounts for 2–5% of all colon cancer cases and approximately 2% of all endometrial cancer (EC) cases. If a reduction of MSH2 expression to 50% is sufficient to increase the rate of telomere shortening in normal differentiated tissues in vivo, there would be an increased risk of early onset of telomere dysfunction leading to cellular senescence in heterozygous carriers that may affect tissue architecture and cancer progression[35]. In this study we have used genotypes of three SNPs in TERT, located on chromosome 5p15.33; rs2736108 (upstream variant) and rs7705526 (intronic variant) both of which have been associated with longer telomeres and breast c ancer[22], and rs2075786 (intronic variant) reported to be associated with shorter telomeres and increased cancer risk in LS29, using data from four different LS cohorts (two of the cohorts previously described for one of the SNPs in[29]). If targeted genetic screening is used to identify patients with further increased risk of developing cancer, more personalized screening strategies may be appropriate to reduce the likelihood of LS patients presenting with cancer
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