Abstract #SY31-3: Lung cancer, smoking, and genetic susceptibility in African Americans
Authors: Ann Schwartz, Angela Wenzlaff, Michele Cote, Alison Van Dyke, Cathryn Bock, Julie Ruterbusch, Susan Land, Wei Chen, Margaret Spitz, Paul McKeigue, Christopher Amos
Journal: Cancer Research (2009)

Lung cancer is the best example of a cancer with undisputed evidence of environmental risk. Although 80-90% of lung cancer incidence can be attributed to cigarette smoking, only 15% of smokers develop this disease suggesting that there are individual differences in susceptibility. Differential risk is also seen by race; African Americans tend to smoke fewer cigarettes and have higher incidence rates for lung cancer than Caucasians. Studies of the genetic contributions to lung cancer risk have included a family-based linkage study, candidate gene studies and genome-wide association studies (GWAS). Several chromosomal regions of interest have been identified, but these studies are complicated by the strong environmental component to risk that is likely driven by addiction-associated genes and most of this work has been conducted in Caucasian populations. Studies in African Americans can provide complementary data to localize lung cancer susceptibility genes and explore smoking dependence-related genes because they represent an admixed population with different patterns of linkage disequilibrium and cigarette use than seen in Caucasians. We conducted several studies to evaluate risk of lung cancer among African Americans associated with chromosomal regions identified in GWAS in Caucasians. We also conducted a gene discovery study based solely in African Americans using admixture mapping. Three GWAS, conducted in European and European American populations, reported an association between non-small cell lung cancer (NSCLC) risk and SNPs on 15q25.1. This region has also been associated with familial lung cancer risk. The region of interest contains nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, and one of the GWAS supports a stronger association with nicotine dependence than lung cancer. To further evaluate risk of lung cancer by race, three SNPs in this region (rs8034191, rs1051730, and rs931794) were genotyped in a pooled sample from 4 population-based case-control studies conducted in metropolitan Detroit that included 1058 cases and 1314 controls. Genotype frequencies varied significantly by race, with minor allele homozygotes accounting for 14% of the Caucasian controls and only 1-5% of the African American controls. Risk associated with rs1051730 (OR=1.6; 95% CI 1.2-2.2) and rs931794 (OR=1.4; 95% CI 1.1-1.7) was increased in ever smoking African Americans after adjusting for pack-years of exposure. This association was not observed in Caucasians where pack-years varied by genotype. Caucasian cases homozygous for the major allele at any of the 3 SNPs smoked for fewer pack-years than cases carrying minor alleles (p 0.88 between any combination of the 3 SNPs. In African Americans the SNPs were not tightly linked; r2 values were 0.20 or less between SNPs. When all 3 SNPs were included in a logistic regression model in a stepwise fashion in African Americans, only rs1051730 was predictive of risk; this SNP is in a linkage disequilibrium block encompassing CHRNA3/CHRNA5. A chromosomal region on 5p15.33 has also been identified as associated with lung cancer risk in GWAS in Caucasian populations. This region includes CLPTM1L, and is adjacent to TERT and SLC6A3. TERT, coding for telomerase reverse transcriptase, has been associated with carcinogenesis, while SLC6A3 codes for the Dopamine Transporter (DAT1) and has been associated with substance abuse and the ability to stop smoking early in a smoking cessation attempt. Several SNPs in these genes were genotyped in a population-based lung cancer case-control study of women in metropolitan Detroit that included 459 cases and 483 controls, of whom approximately 20% were African American. Six of the eight SNPs typed varied significantly in allele frequencies by race. Three of the five TERT SNPs included were significantly associated with risk of lung cancer among African Americans, while only one (rs2853677) was associated with risk among Caucasians in this sample. In stepwise analyses, both rs2075786 and rs2853677 contributed to risk independently in African Americans. SNPs in SLC6A3 were not associated with lung cancer risk in either race group. No significant association was found between genotype at the SLC6A3 or TERT SNPs and mean pack-years of smoking in Caucasian or African American cases. Admixture mapping is an alternative approach to identify markers linked to disease susceptibility that takes advantage of recent admixture among African Americans. The advantage of this approach is that it has greater statistical power than family linkage studies and GWAS to detect disease susceptibility loci if risk alleles are distributed differentially between ancestral groups. To further characterize genetic risk of lung cancer, admixture mapping was used. African American cases and controls were included from the Detroit area pooled analysis described above and from the MD Anderson Cancer Center, for a total of 564 cases and 669 controls. Subjects were genotyped using the Illumina Admixture Panel of 1509 ancestry informative SNPs and the results were analyzed using the software package ADMIXMAP. ADMIXMAP uses a Markov Chain Monte Carlo algorithm to model genotype, phenotype probability distributions based on a priori ancestral allele frequencies. Age, sex, and smoking ever/never were included as covariates. Both affected-only and case-control analyses were conducted. The mean proportions of European admixture in the study populations were 19.7% in Detroit and 23.7% in Texas. In the affected-only analysis, regions on chromosomes 1 and 5 were identified as associated with excess European ancestry, with p-values of   Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY31-3.