Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis - PubMed (original) (raw)

Review

. 2012 Jun 6;104(11):840-54.

doi: 10.1093/jnci/djs222. Epub 2012 Apr 20.

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Review

Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis

Simone Mocellin et al. J Natl Cancer Inst. 2012.

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.

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Figures

Figure 1

Figure 1

Flow chart for the estimation of the joint risk of lung adenocarcinoma in the general population attributable to three TERT locus polymorphisms. Top panel. A forest plot depicting the meta-analysis of the studies that contributed to define the association between the minor alleles of three single-nucleotide polymorphisms (SNPs) and the risk of developing lung adenocarcinoma. Open squares represent odds ratios (ORs) of single studies (the width of each square is proportional to the weight of the corresponding study; the horizontal line represents the 95% confidence interval [CI] of the study OR); solid black diamonds represent summary OR for each SNP (the width of each diamond is proportional to the 95% CI of the corresponding summary OR). Bottom left panel. Only SNP showing strong cumulative evidence for association with lung adenocarcinoma were selected. Cumulative evidence was assessed as per the Venice criteria (see text for more details). OR refer to risk alleles (alleles associated with increased cancer risk). Bottom right panel. The joint PAR (population attributable risk) represents the proportion of lung adenocarcinoma cases estimated to be attributable to the three SNPs showing strong cumulative evidence of association; it depends on both the magnitude of the association (OR) and the risk allele frequency in the general population.

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