Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Abstract

Genome-wide association studies (GWAS) and fine mapping studies have identified multiple lung cancer susceptibility variants in TERT-CLPTM1L region. However, it is still unclear about the relationship between these risk variants and the independent lung cancer risk signals in this region. Therefore, we evaluated the independent susceptibility signals for lung cancer and explored the potential functional variants in this region. Sequential conditional analysis was used to detect the independent susceptibility loci based on four lung cancer GWAS datasets with 12 843 lung cases and 12 639 controls. Comprehensively functional annotations were performed for each independent signal. Three independent susceptibility signals were identified in multi-ethnic population. For the first signal, rs2736100 showed the most significant association with lung cancer risk (C > A, OR = 0.82, 95%CI: 0.79-0.85, P = 1.98 × 10 ). Rs36019446 was the top-ranked site (A > G, OR = 0.88, 95%CI: 0.84-0.92, P = 1.74 × 10 ) in the second signal. For the third signal, rs326048 was the leading SNP (A > G, OR = 0.91, 95%CI: 0.87-0.95, P = 1.38 × 10 ). The following subgroup analysis found the same three loci among Asian population. Further, we compared the difference between various subgroup populations. Functional annotations revealed that rs2736100, rs27996 (r = 0.85 with rs36019446) and rs326049 (r = 0.73 with rs326048) could be potential functional variants in these three risk signals, respectively. In conclusion, although multiple variants have been found associated with lung cancer risk in TERT-CLPTM1L region, our findings indicated that there are three independent lung cancer susceptibility signals in this region.

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

“…Although ERβ plays an important role in CLPTM1L-mediated radioresistance, knockdown of ERβ is not a feasible radiosensitizing method at the moment, because multiple functions of ERβ were still elusive in lung cancer. The present results and those of previous studies suggest that CLPTM1L expression is higher in radioresistant NSCLC cells than in radiosensitive cells, and it is considerably higher than that in normal cells [ 30 , 98 ]. IR upregulated CLPTM1L only in radioresistant cells, whereas it had no effect in most radiosensitive cells.…”

Ethnicity-specific association between TERT rs2736100 (A > C) polymorphism and lung cancer risk: a comprehensive meta-analysis

“…Previous studies also reported that the impact of TERT variation in Asians was stronger than that in Caucasians 45 , 55 . Another study showed that rs2735947 was the most significant SNP in the Caucasians rather than rs2736100 49 . Our findings also confirmed that the C allele and "C" genotype frequencies were indeed higher in Asians than in Caucasians, suggesting that Asians may have longer telomeres that leads to an increased risk of LC.…”

“…These evidences imply that the C allele upregulates TERT expression, maintains and prolongs telomere length, and thus increases the risk of LC. In addition, some studies have conducted racial stratification analysis for different types of LC and proved that the influence of TERT variants in Asians is stronger than that in Caucasians 45 , 49 . These results in turn imply that the frequency of TERT rs2736100 variants varies across ethnic populations.…”

Systematic analysis of genetic variants in cancer-testis genes identified two novel lung cancer susceptibility loci in Chinese population

“…The detailed information about the study subjects in NJMU GWAS was described previously [9]. Genotype imputation for NJMU GWAS was performed using IMPUTE2 and Shapeit v2 with the 1000 Genomes Project (the Phase III integrated variant set release, across 2504 samples) as the reference [14].…”