Telomerase Reverse Transcriptase Locus Polymorphisms and Cancer Risk

A Field Synopsis and Meta-analysis

Simone Mocellin; Daunia Verdi; Karen A. Pooley; Maria T. Landi; Kathleen M. Egan; Duncan M. Baird; Jennifer Prescott; Immaculata De Vivo; Donato Nitti

Disclosures

J Natl Cancer Inst. 2012;104(11):840-854. 

In This Article

Abstract and Introduction

Abstract

Background Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer.
Methods A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association.
Results Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types.
Conclusions To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans.

Introduction

Human telomeres consist of repetitive TTAGGG DNA sequences that associate with a series of telomere binding proteins (shelterin complex) believed to provide genomic stability by protecting the linear chromosome ends from being recognized as DNA breaks to be repaired.[1,2] The inability of the DNA replication machinery to copy the extreme ends of chromosomes, often referred to as the "end replication problem," is consistent with the observation that cells can lose telomeric repeats without initially affecting cell function.[2] Thus, most human somatic cells show progressive telomere shortening with ongoing cell division until a subset of telomeres reach a critically shortened length and induce a DNA damage signal triggering a tumor protein p53 (TP53)–dependent G1/S cell cycle arrest referred to as replicative senescence. Thus, telomeres not only serve as chromosome "caps" to protect chromosome ends from being recognized as DNA damage but also serve as a gauge for the mitotic (replication) age of a cell.[1,2]

The gene encoding the enzyme telomerase reverse transcriptase (TERT), which synthesizes the TTAGGG DNA sequences onto the ends of chromosomes in cooperation with other proteins of the core telomerase complex (eg, telomerase RNA component [TERC] and dyskerin [DKC1]), is located on chromosome 5 (locus 5p15.33). With its activity, telomerase helps maintain the integrity of the genome in embryonic stem cells and in proliferating progenitor cells derived from quiescent normal stem cells.[3,4] Telomerase is silent in the vast majority of human tissues and is only expressed in a small number of normal cell types such as dividing male germline spermatocytes and a subset of proliferating somatic adult stem cells.[4]

In the early 1990s, investigators proposed a connection between telomeres, telomerase, aging, and cancer.[5,6] The hypothesis was that most normal human cells lack telomerase activity and their telomeres shorten with each cell division, until they enter replicative senescence. Cells that lose critical cell cycle checkpoint functions escape this initial growth arrest (replicative senescence) and continue to divide; cells that bypass senescence eventually enter a second growth arrest state (crisis) when many shortened chromosome ends fuse, leading to chromosome bridge–breakage–fusion cycles, which almost universally result in apoptosis.[5] In human cells, these two mechanisms to restrict cell growth (replicative senescence and crisis) are potent anticancer protection mechanisms. Most human cells remain in this crisis period with cell growth being balanced by cell death until a rare cell acquires a mechanism, such as telomerase expression, that can maintain or lengthen telomeres. Cells that have escaped crisis generally have two defining hallmarks, telomere stability and reactivation of telomerase; this rare cell type that can maintain telomeres is then able to grow continuously (ie, becomes immortal), and this is generally believed to be a critical step in cancer progression.[5]

In light of the already abundant evidence linking telomerase activity to the development of many tumor types, many researchers are devising a variety of methods to target telomerase as a novel therapeutic approach potentially useful in a range of cancers;[7,8] moreover, other investigators are testing the hypothesis that variability of the TERT gene sequence might be a general mechanism affecting individual cancer predisposition.[9] Regarding the latter field of investigation, tens of thousands of patients affected with different cancer histotypes have been so far enrolled in molecular epidemiology studies, and some TERT polymorphisms have been reported to be associated with cancer risk, although findings are not always concordant[9] Because there is no synopsis available on this subject, we systematically reviewed the data published to date on the relationship between TERT locus polymorphisms and cancer risk and quantitatively summarized the available evidence by performing a formal meta-analysis.

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