Abstract A81: Germline polymorphisms associated with survival in patients with non-small cell lung cancer
Authors: Schabath Matthew B. , Haura Eric B. , Thompson Zachary J. , Fenstermacher David , Jonathan Kristen A. , Bepler Gerold , Giuliano Anna R. 
Published: June 2012

Introduction: The influence of germline genetic variations in relevant gene pathways on non-small cell lung cancer (NSCLC) prognosis is not well understood. Variations in key gene pathways, such as cell cycle, DNA repair, and drug metabolism, could influence lung cancer patient survival. Methods: We genotyped 1,536 candidate single nucleotide polymorphisms (SNPs) from over 400 different genes in 651 NSCLC patients. Using multivariable Cox proportional hazard models, all SNPs were analyzed for overall survival using an additive-, dominant-, and recessive genetic model. The top 50 significant hits from all three models were ranked and bootstrap resampling was performed 10,000 times to internally validate the results. The data were further analyzed by chemotherapy treatment, stage, and histology.

Results: The overall mean survival time was 35 months. Ranked on P-value, the top five statistically significant SNPs associated with lung cancer survival were (in order): TNFRSF10B:rs11785599 (HR = 1.44; 95% CI 1.18 − 1.75), PLA2G6:rs2284063 (HR = 2.33; 95% CI 1.41 − 3.85), MDM2:rs769412 (HR = 1.68; 95% CI 1.20 − 2.35), FADS2:rs174570 (HR = 1.72; 95% CI 1.20 − 2.43), and CHRNB4:rs6495309 (HR = 1.56; 95% CI 1.15 − 2.13). When the data were analyzed by chemotherapy regimen, all SNPs except for PLA2G6 remained statistically significant among patients treated with platinum agents plus taxane agents. Conversely, none of the SNPs remained statistically significant among patients treated with platinum agents plus gemcitabine agents or among patients not receiving platinum, taxanes, and gemcitabine. When the data were stratified by stage and histology, the top ranked SNP (TNFRSF10B:rs11785599) remained significantly associated with survival (P &lt; 0.003) for early (I + II) and late stage patients (III + IV) and for adenocarcinoma and squamous cell carcinoma. However, differential effects were noted for the other loci. For instance, all five SNPs remained significantly associated with survival among only late stage (III + IV) lung cancers but not early stage (I + II). Moreover, the SNPs in PLA2G6, MDM2, and CHRNB4 were significantly associated with survival only among patients with adenocarcinoma, while the SNP in FADS2 was significantly associated with survival only among patients with squamous cell carcinoma. Age, gender- and smoking-specific effects were also noted.

Conclusions: Overall our results suggest that germline SNPs are associated with NSCLC survival and, specifically, four out of five of the top ranked SNPs (TNFRSF10B:rs11785599, MDM2:rs769412, FADS2:rs174570, and CHRNB4:rs6495309) were significantly associated with survival among patients treated with platinum agents plus taxane agents. If validated, these data have potential important translational implications to optimize patient-specific therapy based on germline genetic profiles.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A81.