2. Population Studies and Disparities Research Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
3. Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD, USA.
4. Applied Genomics Technology Center and Department of Obstetrics & Gynecology, Wayne State University School of Medicine, CS Mott Center. Detroit MI, USA.
5. Preventive Medicine Residency, Department of Epidemiology, University of Michigan School of Public Health, MI, USA.
Background: Germline apoptosis-related single nucleotide polymorphisms (SNPs) have been shown to contribute to the risk of developing non-small cell lung cancer (NSCLC). However, very few studies have looked specifically at apoptosis-related SNPs in a racially-stratified analysis of white and African-American women.
Methods: We examined the risk of developing NSCLC associated with 98 germline SNPs in 32 apoptosis-related genes among women in a population-based case-control study from the Detroit metropolitan area. We examined 453 cases of NSCLC and 478 control subjects. We used an unconditional logistic regression with a dominant model, stratified by race, and adjusted for age, pack-years smoked, ever/never smoking status, family history of lung cancer, history of COPD, BMI and education.
Results: Our logistic regression identified 3 significant apoptosis-related SNPs in whites (APAF-1, rs1007573; CD40 rs3765459, and CD40 rs1535045), and 7 significant SNPs (ATM, rs1801516; BAK1, rs513349; TNF, rs1800629; TP63, rs6790167; TP63, rs7613791, TP63, rs35592567 and TP63, rs3856775) in African-Americans. In a downstream analysis, these SNPs were further prioritized utilizing the False Positive Report Percentage (FPRP) methodology and backwards elimination. In whites, APAF-1 (rs1007573), CD40 (rs3765459) and CD40 (rs1535045) were all found to be significant by FPRP. In African-Americans, TP63 SNPs rs6790167 and rs7613791 were found to have a significant FPRP. In parallel, a backward elimination procedure was used on the 3 significant SNPs in whites and 7 significant SNPs in African-Americans. This procedure identified APAF-1 rs1007573 (OR=1.86, 95% CI:1.17-2.95) and CD40 rs1535045 (OR=0.58, 95% CI:0.40-0.84) as significant independent predictors of risk among whites, and ATM rs1801516 (OR=24.15, 95% CI:3.50-166.55), TNF rs1800629 (OR=0.42, 95% CI:0.18-0.99) and TP63 rs6790167 (OR: 2.85, 95% CI:1.33-6.09) as significant, independent predictors in African-Americans.
Conclusion: In whites, only SNPs APAF-1 rs1007573 and CD40 rs1535045 were significant by both FPRP and backwards elimination, while in African-Americans, only TP63 rs6790167 was significant by both methodologies. Thus, we have identified three promising variants associated with increased risk of NSCLC that warrant additional investigation in future studies.
Keywords: Non-small cell lung cancer (NSCLC), single nucleotide polymorphisms, apoptosis, females, APAF-1, CD40, ATM, TNF, TP63