Telomere length and genetic anticipation in Lynch syndrome

PLoS One. 2013 Apr 23;8(4):e61286. doi: 10.1371/journal.pone.0061286. Print 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Anticipation, Genetic / genetics*
  • Child
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Telomere / genetics*
  • Telomere Shortening

Grants and funding

This work was funded by the Spanish Ministry of Economy (State Secretariat for Research, Development and Innovation) (BFU2009-10281), Carlos III Health Institute (FIS PI08/1635, FIS PI08/1359 and RETIC RD06/0020/1050 and RD06/0020/1051), the Scientific Foundation Asociación Española Contra el Cáncer, the Catalan Government (2009SGR290), and CIBERESP (CB07/02/2005). Nuria Seguí is supported by a fellowship from the Carlos III Health Institute and Laura Valle holds a contract “Ramón y Cajal”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.