Variation at theTERTlocus and predisposition for cancer

Abstract

Telomerase and the control of telomere length are intimately linked to the process of tumourigenesis in humans. Here I review the evidence that variation at the 5p15.33 locus, which contains theTERTgene (encoding the catalytic subunit of telomerase), might play a role in the determination of cancer risk. Mutations in the coding regions ofTERTcan affect telomerase activity and telomere length, and create severe clinical phenotypes, including bone marrow failure syndromes and a substantive increase in cancer frequency. Variants within theTERTgene have been associated with increased risk of haematological malignancies, including myelodysplastic syndrome and acute myeloid leukaemia as well as chronic lymphocytic leukaemia. Furthermore, there is good evidence from a number of independent genome-wide association studies to implicate variants at the 5p15.33 locus in cancer risk at several different sites: lung cancer, basal cell carcinoma and pancreatic cancer show strong associations, while bladder, prostate and cervical cancer and glioma also show risk alleles in this region. Thus, multiple independent lines of evidence have implicated variation in theTERTgene as a risk factor for cancer. The mechanistic basis of these risk variants is yet to be established; however, the basic biology suggests that telomere length control is a tantalising candidate mechanism underlying cancer risk.