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

Sci Rep. 2021 May 31;11(1):11401. doi: 10.1038/s41598-021-90501-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Chromosomes, Human, Pair 5
  • Colorectal Neoplasms / complications
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / complications
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Middle Aged
  • MutS Homolog 2 Protein / genetics*
  • Polymorphism, Single Nucleotide
  • RNA-Directed DNA Polymerase / genetics*
  • Telomerase / genetics*
  • Young Adult

Substances

  • RNA-Directed DNA Polymerase
  • Telomerase
  • MSH2 protein, human
  • MutS Homolog 2 Protein