To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 × 10 −17 ) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.Lung cancer is frequently cited as a malignancy attributable solely to environmental exposures -primarily cigarette smoke. However, evidence that genetic factors influence lung cancer © 2008 Nature Publishing Group Correspondence should be addressed to C.I.A. (E-mail: camos@mdanderson.org). 6 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS Texas: C.I.A. and M.R.S. conceived of this study. M.R.S. established the Texas lung cancer study. C.I.A. supervised and performed the analyses. G.M. provided oversight in manuscript development and in the conduct of genetic studies. I.P.G., Q.D., Q.Z., W.V.C. and X.G. performed statistical analyses. S.S. developed and implemented statistical procedures for joint analysis. X.W. and J. Direct evidence for a genetic predisposition to lung cancer is provided by the increased risk associated with constitutional TP53 (tumor protein p53) 4 and RB1 (retinoblastoma) 5,6 gene mutations, rare mendelian cancer syndromes such as Bloom's 7 and Werner's syndromes 8 , and strongly familial lung cancer 9 . The genetic basis of inherited susceptibility to lung cancer outside the context of these disorders is at present undefined, but a model in which high-risk alleles account for all of the excess familial risk seems unlikely. Alternatively, part of the inherited genetic risk may be caused by low-penetrance alleles. This hypothesis implies that testing for allelic association should be a powerful strategy for identifying alleles that predispose to lung cancer.We conducted a genome-wide association study (GWAS) of histologically confirmed nonsmall cell lung cancer (NSCLC) to identify common low-penetrance alleles influencing lung cancer risk. To minimize confounding effects from cigarette smoking and increase the power to detect genetic effects, we frequency matched controls to cases according to smoking behavior. We also matched controls to cases by age (within 5 year categories) and sex, and we further matched former smokers by year...

Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations.

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.

We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 × 10 −12 ), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; P combined = 4.97 × 10 −10 ) and 5p15.33 (rs401681, CLPTM1L; P combined = 7.90 × 10 −9 ). Support for inherited genetic susceptibility to lung cancer has recently come from genomewide association studies that have demonstrated that 15q25.1 variation influences lung cancer risk 1-3 .To identify risk variants for lung cancer, we carried out a GWA study. Using Illumina HumanHap550 BeadChips, we genotyped 561,466 SNPs in 1,978 cases (Supplementary Methods online). After application of quality control criteria, genotypes were available for 1,952 cases. We were able to satisfactorily genotype 552,947 SNPs (98.5%) with mean sample call rate 99.7%. For controls, we used publicly accessible HumanHap550 genotype data in 1,438 individuals from the 1958 Birth Cohort 4 (Supplementary Methods). Genotypes were available for 541,327 SNPs (97.5% of 555,352 SNPs typed) and 524,714 SNPs were common to cases and controls. Applying quality control filters, we excluded 8,534 SNPs monomorphic in either cases or controls; 2,744 with call rates < 95%; 770 showing departure from HardyWeinberg equilibrium (HWE; P < 10 −5 in cases or controls) and 747 with minor allele frequency (MAF) <1% in cases or controls; leaving 511,919 informative SNPs for analysis.

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