For a general phenotypic description and a discussion of genetic heterogeneity of lung cancer, see 211980.

In a genomewide association study of 3,259 patients with lung cancer and 4,159 controls, McKay et al. (2008) found a significant association between lung cancer and 2 SNPs, rs402710 and rs2736100 on chromosome 5p15.33 (p = 2 x 10(-7) and p = 4 x 10(-6), respectively). The findings were replicated in 2,899 cases and 5,573 controls (p = 7 x 10(-5) and p = 0.016 for the 2 SNPs, respectively). The susceptibility region on chromosome 5p15 contains 2 genes, TERT (187270) and CLPTM1L (612585), suggesting that 1 or both may have a role in lung cancer etiology.

Wang et al. (2008) found a significant association between rs401681 on chromosome 5p15.33 and lung cancer susceptibility in a genomewide association study of 5,095 cases of lung cancer and 5,200 controls. The findings were replicated in an additional 2,484 cases and 3,036 controls (p value = 7.90 x 10(-9)). The A allele of rs401681 was associated with decreased risk of lung cancer. The SNP is located within intron 13 of the CLPTM1L gene.

Given the relevance of the 5p15.33 region to cancer biology, and following confirmation of association of SNPs within the region with risk of basal cell carcinoma (605462), Rafnar et al. (2009) assessed the association of the SNP rs401681 with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls. They found association of the C allele with lung cancer (OR = 1.15, p = 7.2 x 10(-8)) and weaker associations with urinary bladder, prostate, and cervix cancer. Notably, most of these cancer types have a strong environmental component to their risk. The lung cancer study included 4,265 patients and 34,666 controls.

In a genomewide association study of lung cancer and its major histologic types involving 515,922 SNPs and 5,739 lung cancer cases and 5,848 controls, Landi et al. (2009) found an association between TERT SNP rs2736100 and the risk of adenocarcinoma (odds ratio, 1.23; corrected p = 3.02 x 10(-7)). Metaanalysis combining their results with summary data from 10 previous studies for a total of 13,300 cases and 19,666 controls replicated the finding (odds ratio, 1.24; corrected p = 3.74 x 10(-14)). Landi et al. (2009) concluded that the previously identified association of rs2736100 on chromosome 5p15.33 with lung cancer risk is confined to the adenocarcinoma histologic type, and noted that rs2736100 is located in intron 2 of TERT within a putative regulatory region.

Hu et al. (2011) performed a genomewide association scan of 5,408 subjects (2,331 individuals with lung cancer and 3,077 controls) followed by a 2-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified 6 well-replicated SNPs with independent effects and significant lung cancer associations. Hu et al. (2011) confirmed the locus at 5p15.33 in the TERT-CLPTM1L region characterized by rs465498 and rs2736100 (p = 1.2 x 10(-20) and p = 1.0 x 10(-27), respectively). The authors also confirmed an associated SNP, rs4488809 (see LNCR5, 614210), located in the first intron of TP63 (603273) on chromosome 3q28 (p = 7.2 x 10(-26)).