The differences in genetic association across the geographical regions of the Indian subcontinent, comprised of distinct population groups, might be attributed to gene–gene and gene-environment interactions, which could act as potential modulators of lung cancer risk 34. Contradictory outcomes of case–control association studies of the same polymorphism by different authors failed to identify the genes' overall effect and the genetic variations on lung cancer susceptibility in the region. Most of the GWAS was done on European or Chinese descent subjects, and the majority of the identified risk alleles have not been evaluated in the population of the Indian subcontinent despite several candidate gene association studies 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. Out of the 10 loci, four were associated with overall lung cancer risk, while the remaining 6 loci were associated with lung adenocarcinoma 21. Interestingly, the association of the 10 novel loci varied across different histological subtypes. Similarly, another GWAS on subjects of European ancestry with 29,266 lung cancer patients and 56,450 controls identified 18 susceptibility loci ( p ≤ 5.00 × 10 −8), including 10 novel loci 21. Genome-wide association studies (GWAS) in the Chinese population have identified 16 susceptibility loci (p ≤ 5.00 × 10 −8) associated with lung cancer risk 22, 23, and 4 loci out of them showed evidence of association with lung cancer risk in smokers 22. Earlier studies have revealed a rise in lung cancer incidence among never smokers 19, particularly in women of East Asian origin 20, 21. Apart from tobacco smoking, betel quid chewing 8, 9, diet 10, 11, 12, biofuel exposure 10, 11, 12, 13, 14, 15, asbestos exposure 10, 11, 16 and other environmental pollutants 10, 11, 17, 18 contribute to lung carcinogenesis. Smoking tobacco is considered the most significant factor in lung carcinogenesis 1, 7.
Earlier reports stated that approximately one million of the total five million lung cancer deaths worldwide are contributed by India 5, and the death toll is projected to rise to 1.5 million by 2020 5, 6. The northeastern state of Mizoram accounts for the highest reported cases of lung cancer in both sexes 4.
In India, lung cancer constitutes 5.9% of all new cancer cases and 8.1% of all cancer-related mortalities in both sexes 2. Lung cancer incidences vary widely across geographical regions due to the admixture of different populations 4. A recent investigation has shown the increase in lung cancer incidence in the Indian subcontinent and East Asia 3. Epidemiological data suggest that the global lung cancer burden has risen to 2.1 million new cases of all cancer cases and 1.8 million deaths, close to 1 in 5 cancer deaths 2. This study identified the susceptibility loci for lung cancer and its covariate-subgroups.ĭespite several measures taken against tobacco smoking and consumption, lung cancer remains one of the leading causes of cancer-related mortalities worldwide, with a low 5-year survival rate 1. Genotyping of rs1048943/ CYP1A1 that presented significant heterogeneity ( p < 0.1) revealed an association with adenocarcinoma among eastern Indian smokers, while a global meta-analysis in 10458 cases and 10871 controls showed association with lung cancer and its subgroups. Association of rs4646903/ CYP1A1 in smokers and effect modification by meta-regression analysis was observed. Subtype analysis showed a significant association of del1/ GSTT1 with adenocarcinoma, rs4646903/ CYP1A1 with squamous carcinoma, and rs1048943/ CYP1A1 with both.
Meta-analysis of 18 variants of 11 genes reported in 39 studies (7630 cases and 8169 controls) showed significant association of rs1048943/ CYP1A1 and rs4646903/ CYP1A1 with overall lung cancer risk at 10% FDR, while nominal association ( p < 0.05) was observed for del1/ GSTT1, del2/ GSTM1, rs1695/ GSTP1 and rs17037102/ DKK2. We genotyped and investigated rs1048943/ CYP1A1 in a case–control sample from eastern India, followed by its global meta-analysis using a similar protocol. Multiple testing corrections were done by the Benjamini–Hochberg method through assessment of significance at a false discovery rate of 10%. We performed a meta-analysis of candidate associations on lung cancer, its histological subtypes and smoking status in the Indian subcontinent following PRISMA guidelines.
To summarise and replicate published evidence for association with lung cancer and its subgroups. Reports of genetic association of polymorphisms with lung cancer in the Indian subcontinent are often conflicting.
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