A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants

• Published in: Scientific reports Vol. 11; no. 1; p. 11401
• Main Authors: Wiik, Mariann Unhjem, Evans, Tiffany-Jane, Belhadj, Sami, Bolton, Katherine A., Dymerska, Dagmara, Jagmohan-Changur, Shantie, Capellá, Gabriel, Kurzawski, Grzegorz, Wijnen, Juul T., Valle, Laura, Vasen, Hans F. A., Lubinski, Jan, Scott, Rodney J., Talseth-Palmer, Bente A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208; 631/208/68; Cancer; Colorectal cancer; Colorectal carcinoma; Gene polymorphism; Genetic disorders; Genetic diversity; Genetic variance; Genotype & phenotype; Health risks; Humanities and Social Sciences; MLH1 protein; MSH2 protein; MSH6 protein; multidisciplinary; RNA-directed DNA polymerase; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Telomerase; Telomerase reverse transcriptase
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-90501-2

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.