Taken together, our results establish a protumorigenic role for CLPTM1L that is critical for Ras-driven lung cancers, with potential implications for therapy and chemosensitization.
The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10(-8)) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10(-26)), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10(-20) and P = 1.0 × 10(-27), respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10(-12)) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10(-11) and P = 6.2 × 10(-13), respectively).
Taken together, our results establish a protumorigenic role for CLPTM1L that is critical for Ras-driven lung cancers, with potential implications for therapy and chemosensitization.
Recent genome-wide association studies and consecutive validation supported that the 5p15.33 region containing telomerase reverse transcriptase gene (TERT) and cleft lip and palate transmembrane protein 1-like (CLPTM1L) gene showed significant association with lung cancer in multiple populations.
In conclusion, our study indicated that the CLPTM1L - rs401681 (G>A) polymorphism was significantly associated with decreased lung cancer risk, especially among European populations.
Common genetic polymorphisms on chromosome 5p15.33, including rs401681 in cleft lip and palate transmembrane 1-like gene (CLPTM1L), have been implicated in susceptibility to lung cancer through genome-wide association studies (GWAS); however, subsequent replication studies yielded controversial results.
CLPTM1L transferred lung cancer cell line 95-D showed no growth inhibition or cell apoptosis, but it did show inhibited sensitivity to cis-diamminedichloroplatinum(II) (cisplatin, CDDP).
In the logistic regression analysis, TERT-rs2853669, rs2736108, and CLPTM1L-rs31490 were significant associated with increased risk of lung cancer (OR = 1.46, 95% CI = 1.22-1.75; OR = 1.22, 95% CI = 1.00-1.49 and OR = 1.74, 95% CI = 1.35-2.23 under additive model, respectively).
These data demonstrate a potential association between the TERT-CLPTM1L variant and levels of bulky DNA adducts measured by (32)P-postlabeling and hence a basis for susceptibility to the development of lung cancer.
We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus.
We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four 'control' genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies.