Abstract IA03: Lung cancer risk in African Americans: Familial aggregation and genetic susceptibility

Lung cancer is the most common cause of cancer death in the United States with 158,040 deaths estimated in 2015 (accounting for 27% of all cancer deaths), and the second most frequent cancer diagnosed, behind breast cancer in women and prostate cancer in men, with 221,200 new diagnoses estimated in 2015. Incidence among African American men is 1.3-fold higher than among white men, while incidence among African American women is similar to that among white women. These disparities exist even though African Americans tend to smoke fewer cigarettes per day than whites. Survival remains poor, with five-year survival of about 17%. The five-year survival rate has changed little over time because lung cancers are still most often diagnosed at advanced stages when treatment is less effective. Cancer of the lung has frequently been cited as an example of a malignancy that is solely determined by the environment; 80-90% of all lung cancers are attributable to cigarette smoking. However, there is consistent evidence in support of a genetic contribution to lung cancer susceptibility, first defined by studies of familial aggregation followed by family-based linkage studies and genome-wide association studies (GWAS). Epidemiologic evidence demonstrates familial aggregation of lung cancer after adjusting for familial clustering of cigarette smoking and other risk factors, with variation in risk by race. Familial aggregation of lung cancer was first reported 5 decades ago. The most recent pooled analysis, from the International Lung Cancer Consortium including data from approximately 24,000 lung cancer cases and 23,000 controls, reported a significant 1.5-fold increased risk of lung cancer associated with family history after adjustment for smoking and other potential confounders in cases and controls, and a significant 1.25-fold increased risk for never smokers. The best designed of these studies takes into account the number of relatives in the families and the risk factor profile of each relative so that the effect of familial clustering of smoking habits can be taken into account. When only studies that had risk factor data for each family member were included, relative risk (RR) estimates for lung cancer among relatives with a family history were 1.55 overall, 1.53 for white, 2.09 for African American, and 1.97 for early-onset ( Family-based linkage analysis has been used to detect genetic loci that are rare and highly penetrant (after adjusting for environmental risk factors). The Genetic Epidemiology of Lung Cancer Consortium (GELCC) has conducted linkage analyses in very high risk lung cancer families. The strongest evidence for linkage was on chromosome 6q23-25. In this region, lung cancer risk among putative carriers was higher than among noncarriers, even among never smokers. Lung cancer risk among smoking noncarriers demonstrated the usual dose response curves, with increasing risk associated with increasing amount smoked. Among smoking carriers, while risk was higher than among noncarriers, the usual dose response curves were not evident suggesting that any level of tobacco exposure increases risk among those with inherited lung cancer susceptibility. A germline mutation in PARK2 has been linked to lung cancer in a very high risk family with 8 affected members. Additional evidence suggestive for linkage was also found for regions on chromosome 1q, 8q, 9p and 12q, 5q, 14q and 16q. Interrogation of all these regions is ongoing, using standard family-based linkage methods and whole genome or whole exome sequencing. Little has been done specifically by race in families. The search for more common, low penetrance genes with modest effects has been conducted in admixture mapping studies and more recently in GWAS. GWAS have provided highly significant and reproducible results for lung cancer associations on a 15q25 region that spans several nicotine receptor genes (CHRNA3, CHRNA5), a region also associated with COPD, lung function and nicotine addiction. GWAS also identified regions on chromosomes 6p21 (BAT3 and MSH5) and 5p15 (TERT and CLPTM1L) as being associated with lung cancer. These studies were limited to individuals of European ancestry. While GWAS have also been conducted in Asian populations, with similar results, less has been done in African American populations. Associations identified in individuals of European ancestry on 15q25, 5p15 and 6p21 have been replicated in African Americans. The strongest associations in African Americans were seen on 15q25.1, with histology-specific findings on 6p22-21 and 5p15. No GWAS results in African Americans have been published to date, although one is underway at NCI. GWAS in other races/ethnic groups with different linkage disequilibrium and smoking patterns than seen in individuals of European ancestry is a powerful approach for narrowing regions of interest by providing complementary data to help localize lung cancer susceptibility genes. In summary, substantial racial differences in lung cancer incidence and survival exist. There is strong evidence supporting a genetic contribution underlying lung cancer susceptibility, with multiple genetic loci under investigation. The identification of susceptibility genes for lung cancer is of major public health importance because it allows for the targeting of a high risk group for smoking prevention/cessation interventions and for lung cancer screening programs. It will also provide new understanding of the mechanism of carcinogenesis and may suggest better methods of prevention and targeted treatment. There remain challenges due to lung cancer heterogeneity at multiple levels: by histologic types, exposures to various individual risk factors, and susceptibility loci. There is also the potential for gene-environment interactions and gene-gene interactions. The study of diverse populations will only aid in our understanding of the genetics of lung cancer. Citation Format: Ann G. Schwartz. Lung cancer risk in African Americans: Familial aggregation and genetic susceptibility. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA03.