Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never‐smoking women in Asia: a report from the female lung cancer consortium in Asia

Abstract

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of 7 telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women’s Health study, we demonstrated the utility of a genetic risk score (GRS) of 7 telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI=1.34–1.69) for upper vs. lower quartile of the weighted GRS, P-value=4.54×10−14) even after removing rs2736100 (P-value=4.81×10−3), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

“…Alternatively, upregulated telomerase activity leading to increased telomere length may also promote tumorigenesis by conferring properties of immortal growth [3]. Indeed, recent studies suggest longer telomere length may be a risk factor for select tumor types including melanoma, lung cancer, chronic lymphocytic leukemia, glioma, and ovarian cancer [4–7]. …”

“…Recent studies have evaluated the relationship between these genetic proxies of telomere length and risk of cancer and found evidence suggesting longer genetically inferred telomere length is associated with increased cancer risk [4–7]. The approach employed by these studies, Mendelian randomization, uses genetic variants associated with leukocyte telomere length as genetic instruments to investigate the relationship between leukocyte telomere length and RCC risk.…”

Leukocyte Telomere Length in Newborns: Implications for the Role of Telomeres in Human Disease

“…[40][41][42][43] Jointly, alleles of SNPs that are associated with a short LTL increase the genetic risk for atherosclerosis, 40 whereas alleles of the same SNPs that are associated with a long LTL increase the risk for some cancers. 44,45 It is reasonable to infer causality when not only LTL but also that gene variants related to LTL are associated with atherosclerosis and cancer.…”

An Overview of Genetic Polymorphism and Lung Cancer Risk

“…The association for this variant was validated in one study of female lung cancer patients with no history of smoking in Asian populations [16]. BPTF protein is required for c-MYC transcriptional activity [38,39] and somatic alterations in BPTF have been detected in a small percentage of ADC tissue samples [2,30,39]. However, further studies are needed to determine whether BPTF is responsible for susceptibility to ADC.…”

“…The rs2736100 SNP is associated with susceptibility to other cancer types, including cancers of the brain, bladder, prostate, uterine cervix, and skin, as well as testicular cancer and chronic lymphocytic leukemia [28,29]. There are conflicting results regarding the association between the TERT SNPs and telomere length in leukocytes [28,30]. However, variants in the TERT promoter region (rs2853669 and rs2735940) and intron 4 (rs10069690) are likely to affect telomere length in leucocytes or noncancerous tissues [31,32].…”