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

Results

Literature Search

We found 6497 potentially relevant articles, and retrieved 66 articles[18,21–84] reporting on 85 case–control studies that assessed the association between TERT locus polymorphisms and cancer risk, and met the eligibility criteria (Supplementary Figure 1, available online). They were published in a relatively limited time span (2003–2011), witnessing the recent interest in this molecular epidemiology field. We identified 494 allelic contrasts after including ethnicity and tumor subtype–specific data, whose details are reported in Supplementary Table 1, available online.

Overall, data were available on 67 polymorphisms and 24 tumor types, with 490 901 subjects being genotyped (195 305 case subjects and 295 596 control subjects): the 221 unique combinations of TERT locus polymorphisms with cancer types are depicted in a heat map (Supplementary Figure 3, available online), which also includes information on number of studies, type of association (statistically significant vs non–statistically significant), and the level of evidence (strong, moderate, and weak) for association. Considering the total number of case and control subjects enrolled in the eligible studies, TERT locus polymorphisms were most frequently investigated in lung cancer (56 682 subjects; 29.0%), the only tumor type for which data on histological subtypes could be included in the meta-analysis; the other five most frequently studied tumor types were prostate (47 294 subjects; 24.2%), colon (16 279 subjects; 8.3%), breast (15 090 subjects; 7.7%), and bladder (10 202 subjects; 5.2%) carcinomas, and central nervous system (CNS) tumors (8795 subjects; 4.5%).

The median number of subjects enrolled per study was 2771 (range: 125–79 600). White subjects of European ancestry was by far most frequently involved (425 010 subjects; 86.5%), Asian ethnicity representing virtually all the remaining subjects. In the majority of the studies (58 of 85), selected TERT locus polymorphisms were investigated, whereas the remaining 27 were GWAS. All variants were single-nucleotide polymorphism (SNP), except for two minisatellite polymorphisms (TERT MNS16a and VNTR2-2nd) and one deletion (TERT Glu441del).

Among the 485 allelic contrasts for which an odds ratio could be calculated, 233 (48%) showed a statistically significant association with risk of cancer (Supplementary Table 1, available online). Available data enabled us to perform 118 meta-analyses (including 41 subgroup analyses based on specific ancestries and histological subtypes) for 35 polymorphisms tested in one or more different tumor types and for which at least two studies were available. The main findings of these meta-analyses reporting 75 (64%) statistically significant associations and 43 (36%) non–statistically significant associations between TERT locus polymorphisms and cancer are shown in Table 1 and Table 2, respectively.

Overall, 22 polymorphisms were associated with the risk of developing one or more types of cancer but only 11 showed strong cumulative evidence according to the international guidelines known as Venice criteria (moderate and weak cumulative evidence was found for nine and 14 polymorphisms, respectively). In particular, among the 75 allelic contrasts for which the meta-analysis showed statistically significant associations with cancer risk, the cumulative evidence was strong, moderate, and weak for 20 (27%), 15 (20%), and 40 (53%) allelic contrasts, respectively. The results for polymorphisms with strong evidence of an association with at least one tumor type are described below. Findings for each polymorphism are detailed in the Supplementary Results (available online). Finally, for five (12%) of the 43 meta-analyses that showed no statistically significant association, the cumulative evidence for lack of association with cancer risk was strong.

Associations between TERT Locus Polymorphisms and Cancer Risk

rs2736098. Although rs2736098 is a synonymous polymorphism (G>A; Ala305Ala), this TERT SNP has been shown to be associated with telomere length but not with TERT expression.[41] On the other hand, rs2736098 is in LD with rs2853669 (pairwise correlation coefficient r2 = 0.79),[24] an SNP granted functional relevance (see Supplementary Results, available online). Therefore, rs2736098 may simply be a marker tagging the relevant polymorphism.

Meta-analysis by tumor type revealed a statistically significant association between the minor allele rs2736098[A] and both lung (OR = 1.21, 95% CI = 1.15 to 1.27) and bladder cancer (OR=1.19, 95% CI = 1.12 to 1.25) (Table 1). According to the Venice criteria, the cumulative evidence for the association between rs2736098[A] and the risk of these two tumor types was strong. Because the MAF of rs2736098 was 26%, the estimated PAR for lung and bladder cancer was 6% and 5%, respectively. Meta-analysis of available data showed no association between this SNP and either prostate cancer or CNS tumors (Table 2).

rs2736100. SNP rs2736100 is located in intron 2 of TERT and, on the basis of the Evolutionary and Sequence Pattern Extraction through Reduced Representation (ESPERR) score,[85] is located within a putative regulatory region.[40] This polymorphism has also been linked to idiopathic pulmonary fibrosis, a disease associated with increased risk of developing lung cancer.[86] It is also the most studied polymorphism of the TERT gene, as it was described in 46 studies enrolling 74 785 case subjects with 11 tumor types and 115 726 control subjects.

Thirty-two studies reported a statistically significant association between the minor allele rs2736100[C] and cancer susceptibility. Notably, for testicular cancer, this allele was associated with a decreased disease risk, whereas for all other tumor types, it was associated with an increased disease risk. Upon meta-analysis, the association between this TERT polymorphism and cancer risk was statistically significant for lung, bladder, pancreatic, testis, and CNS tumors (Table 1), but not melanoma (data for melanoma is presented in Table 2). Lung cancer was by far the most studied tumor type, with 50 917 case subjects and 72 598 control subjects enrolled in 23 studies. The meta-risk was highly statistically significant (OR = 1.19, 95% CI = 1.14 to 1.23), but with a large amount of heterogeneity (I 2 = 77%, P < .001), which made the cumulative evidence for association weak. A stronger association was noted in Asians (OR = 1.26, 95% CI = 1.20 to 1.32) compared with whites (OR = 1.11, 95% CI = 1.08 to 1.15; P heterogeneity for difference between ORs < .001); however, the cumulative evidence remained weak for both ancestries because of the small overall association among whites and the large heterogeneity (I 2 = 68%, P < .001) coupled with potential chasing bias (Ioannidis and Trikalinos test P = .035) among Asian studies.

Because data were permissive, we investigated this SNP also in relation with lung cancer subtypes. The risk of adenocarcinoma was highest among all subtypes (OR = 1.30, 95% CI = 1.25 to 1.36), but again, the cumulative evidence was weak as a result of lack of replication and large heterogeneity (I2 = 62%, P = .001). However, when ethnicity was taken into account, the risk among whites was highly statistically significant (OR = 1.22, 95% CI = 1.17 to 1.27) and the cumulative evidence was strong (estimated PAR = 11%, MAF = 45%). The association of rs2736100 with adenocarcinoma was reported to be stronger among never smokers,[65] a population subset where this is the most common form of lung cancer. Moreover, the estimated joint PAR for three polymorphisms including TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710 was 41% (Figure 1). Among Asians, the meta-risk for this tumor subtype was higher (OR = 1.35, 95% CI = 1.29 to 1.42, P heterogeneity < .001), but heterogeneity remained statistically significant (I 2 = 47%, P = .067) and the cumulative evidence for association was moderate.

For squamous cell carcinoma, the meta-risk point estimate was small for rs2736100[C] (OR = 1.06, 95% CI = 1.01 to 1.12) and the cumulative evidence for association was weak. For small cell lung cancer, the cumulative evidence for lack of association (OR = 1.05, 95% CI = 0.99 to 1.09) was strong (Table 2). Other subgroup analyses performed for lung cancer are reported in Table 1.

rs2736100[C] was statistically significantly associated with reduced risk of testicular germ cell carcinoma (TGCC) (OR= 0.75, 95% CI = 0.70 to 0.81), the cumulative evidence for association was strong (estimated PAR for the risk allele rs2736100[A] = 22%, risk allele frequency = 55%).

For other tumor types, no strong evidence could be demonstrated. For pancreatic cancer, the available data were in favor of a small risk increase (OR = 1.12, 95% CI = 1.04 to 1.20) and the cumulative evidence was weak. The association of rs2736100[C] with the risk of bladder carcinoma was also statistically significant (OR = 1.19, 95% CI = 1.05 to 1.34), but because of the relatively low number of subjects enrolled (100 < n < 1000, n = subjects carrying the minor allele), the cumulative evidence was moderate. Finally, the association with risk of CNS tumors was even stronger (OR = 1.34, 95% CI = 1.22 to 1.46), but the cumulative evidence for association was weak as a result of large heterogeneity (I 2 = 60%, P = .02).

rs2853676. The association of this TERT intronic polymorphism with risk of cancer was evaluated in 18 studies, including 31 481 case subjects (11 tumor types) and 44 122 control subjects. Four studies on CNS tumors and one on cutaneous melanoma reported a statistically significantly increased risk for carriers of the minor allele (A), whereas one study described a reduced risk for TGCC. Meta-analysis by tumor type revealed a strong association between rs2853676[A] and increased risk of CNS tumors (OR = 1.26, 95% CI = 1.21 to 1.32), and the cumulative evidence was strong (estimated PAR = 7%, MAF = 24%).

In contrast, the cumulative evidence for lung cancer risk was weak, because of a small meta-risk (OR = 1.06, 95% CI = 1.01 to 1.10). Finally, no association could be demonstrated for pancreatic cancer (OR = 0.93, 95% CI = 0.86 to 1.00) and melanoma (OR = 1.16, 95% CI = 0.81 to 1.66).

rs31489. This intronic SNP of the CLPTM1L gene was chosen because it is located in a DNA region in LD with the TERT promoter and the 5′-end of TERT gene (Supplementary Figure 1, available online).[9] Nine studies reported statistically significant association between cancer risk and the minor allele (A), but with opposite risk directions for lung cancer and skin basal cell carcinoma (BCC) (decreased) as compared with pancreatic cancer and TGCC (increased).

Meta-analysis by tumor type confirmed that rs31489[A] is associated with an increased risk of pancreatic cancer (OR = 1.18, 95% CI = 1.06 to 1.32) and TGCC (OR = 1.28, 95% CI = 1.16 to 1.41) but is statistically significantly associated with reduced risk of lung cancer (OR = 0.83, 95% CI = 0.78 to 0.88) (Table 1). The cumulative evidence for association was strong only for testicular cancer (estimated PAR = 11%, MAF = 36%). For the other tumor types, no meta-analysis could be performed.

rs380286. This SNP is located in an intronic region of CLPTM1L. Two studies reported that subjects carrying the minor allele (A) were associated with reduced risk of lung cancer (OR = 0.85, 95% CI = 0.80 to 0.91), and the cumulative evidence was strong (estimated PAR for risk allele rs380286[G] = 13%, major allele frequency = 63%) (note that in this case the "risk" allele coincides with the "major" allele).

rs401681. This SNP is located in an intronic region of CLPTM1L. Like rs2736098, rs401681 was reported to be associated with telomere length (but not TERT expression),[41] which supports its relevance for telomere biology and potentially cancer development. At present, rs401681 is the most widely studied TERT locus polymorphism because it was assessed for cancer risk in 56 series enrolling 89 903 case subjects (23 tumor types) and 155 202 control subjects (Supplementary Table 1, available online). In 29 studies, a statistically significant association was observed between the minor allele (T) and cancer risk; however, 21 studies described a decreased cancer risk, whereas eight described an increased risk.

Meta-analysis by cancer type revealed that rs401681[T] carriers have a modestly increased risk of pancreatic carcinoma (OR = 1.14, 95% CI = 1.01 to 1.29) and skin melanoma (OR = 1.12, 95% CI = 1.03 to 1.22). Conversely, a modest risk reduction was observed for bladder (OR = 0.89, 95% CI = 0.86 to 0.92), lung (OR = 0.87, 95% CI = 0.84 to 0.89), and prostate (OR = 0.92, 95% CI = 0.89 to 0.95) cancer and skin squamous cell carcinoma (OR = 0.92, 95% CI = 0.84 to 0.99). Finally, a more pronounced risk reduction was detected for BCC (OR = 0.82, 95% CI = 0.76 to 0.89). In no case was the cumulative evidence strong because of between-study heterogeneity and/or small overall association (Table 1).

For lung cancer, available data also enabled us to perform meta-analysis by ancestry and histological subtype. SNP rs401681[T] was associated with statistically significantly reduced risk of both adenocarcinoma (OR = 0.87, 95% CI = 0.81 to 0.93) and squamous cell carcinoma (OR = 0.85, 95% CI = 0.76 to 0.96), but not with small cell lung cancer (OR = 0.98, 95% CI = 0.90 to 1.07). Nevertheless, the cumulative evidence for the first two lung cancer subtypes was weak because of heterogeneity (Table 1). When ethnicity was taken into account, a reduced risk of non–small cell lung carcinoma was observed only among Asians (OR = 0.84, 95% CI = 0.79 to 0.90), and the cumulative evidence for association was strong (estimated PAR for risk allele rs401681[C] = 13%, major allele frequency = 60%).

Finally, no statistically significant relationship was observed for the other tumor types (breast, colon, endometrial cancer, and TGCC) for which a meta-analysis could be performed; for breast and colon carcinomas, the cumulative evidence for lack of association was strong (Table 2).

rs402710. This CLPTM1L intronic SNP is in LD with many other CLPTM1L polymorphisms, including the above described rs401681 (see Supplementary Figure 2, available online), but not with TERT polymorphisms such as rs2736100, which led some authors to postulate that that the 5p15.33 locus might host two independent cancer risk SNPs (ie, rs2736100 and rs402710).[29] Ten studies reported a statistically significant association between the minor allele (T) and a decreased risk of lung, bladder, and nasopharyngeal tumors, whereas two other studies described the opposite relationship with pancreatic and testicular cancer (Supplementary Table 1, available online).

Upon meta-analysis, rs402710[T] was associated with reduced risk of both bladder (OR = 0.85, 95% CI = 0.75 to 0.98) and lung cancer (OR = 0.87, 95% CI = 0.83 to 0.92), but in neither case was the cumulative evidence for association strong (Table 1).

Available data allowed a meta-analysis of lung cancer histological subtypes for risk assessment. Interestingly, rs402710[T] showed a homogeneous and statistically significantly reduced risk of both adenocarcinoma (OR = 0.84, 95% CI = 0.80 to 0.89) and squamous cell carcinoma (OR = 0.83, 95% CI = 0.77 to 0.89), the cumulative evidence being strong in both subtypes (estimated PAR for risk allele rs402710[C] = 14%, risk allele frequency = 66%). Finally, no statistically significant association was found with the risk of pancreatic cancer (OR = 1.14, 95% CI = 0.98 to 1.32).

rs4635969. Considering the minor allele (A) of this TERT/CLPTM1L intergenic SNP, available studies reported opposing but statistically significant findings for lung cancer (decreased risk) and both pancreatic cancer and TGCC (increased risk). Meta-analysis by tumor type confirmed an association between rs4635969[A] and reduced risk of lung cancer (OR = 0.86, 95% CI = 0.82 to 0.90), although the cumulative evidence was weak because of a small overall association. As also reported for rs2736100, the reduced risk was more pronounced in lung adenocarcinoma (OR = 0.81, 95% CI = 0.75 to 0.88), for which the cumulative evidence for association could be classified as strong (estimated PAR for risk allele rs4635969[G] = 23%, major allele frequency = 80%).

Among rs4635969[A] carriers, the risk was statistically significantly increased for pancreatic (OR = 1.22, 95% CI = 1.14 to 1.32) and testicular (OR = 1.61, 95% CI = 1.46 to 1.76) carcinomas. In these two cancers, the overall evidence for association was strong, the estimated PAR being 5% and 14%, respectively. Of note, the meta-risk for TGCC associated with this SNP was the strongest association found in the present meta-analysis.

rs465498. All four studies evaluating this intronic CLPTM1L SNP found a statistically significantly reduced cancer risk in people carrying the minor allele (G). Pooling the summary data confirmed this association (OR = 0.79, 95% CI = 0.74 to 0.84), although the cumulative evidence for association appeared moderate as a result of heterogeneity (I 2 = 49%, P = .12). Restricting the analysis to the Asian ancestry by pooling data from three series (a GWAS with one discovery and two independent replication phases) resulted in a homogeneous (I 2 = 0%, P = .76) and statistically significant association with reduced risk of cancer (OR = 0.76, 95% CI = 0.72 to 0.81), which was statistically significantly lower (P heterogeneity = .021) than that reported in the study restricted to white subjects (OR = 0.85, 95% CI = 0.79 to 0.92), and the cumulative evidence was strong (estimated PAR for risk allele rs465498[A] among Asians = 36%, major allele frequency among Asians = 83%).

rs467095. The three studies reporting on the allele distribution of this intronic CLPTM1L polymorphism described a reduced cancer risk in people carrying the minor allele (C). Pooling the summary data confirmed the association of rs467095[C] with reduced cancer risk (OR = 0.83, 95% CI = 0.78 to 0.85), and the cumulative evidence for association was strong (estimated PAR for the risk allele rs467095[T] = 17%, major allele frequency ≈ 72%).

MNS16a. This variable tandem repeat polymorphism (short [S] vs long [L] polymorphism) is located downstream of the TERT gene and was reported to affect promoter activity in lung cancer cell lines,[21] although the functional importance of the antisense transcript activity is unclear. Two studies on CNS tumors and one on breast cancer reported that the minor allele (S) was associated with an increased risk of disease development.

The meta-analysis showed that MNS16a[S] is associated with a homogeneously reported (I 2 = 8%, P = .30) statistically significantly increased risk of CNS tumors (OR = 1.20, 95% CI = 1.07 to 1.33; I 2 = 8%, P = .30), but not breast (OR = 1.20, 95% CI = 0.84 to 1.71) or lung (OR = 0.99, 95% CI = 0.62 to 1.60) carcinomas. The cumulative evidence for association between MNS16a[S] and CNS tumors was strong (estimated PAR = 7%, MAF = 34%).

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