title: Hypoxia pathway genetic variants predict survival of non-small-cell lung cancer patients receiving platinum-based chemotherapy.
abstract: Hypoxia is a hallmark of solid tumors and has been implicated in the development of advanced disease and poor clinical outcome. In this multi-stage study, we aimed to assess whether genetic variations in hypoxia pathway genes might affect overall survival (OS) in patients with advanced-stage non-small cell lung cancer (NSCLC). We genotyped 598 potentially functional and tagging single nucleotide polymorphisms (SNPs) in 42 genes of the hypoxia pathway in 602 advanced stage NSCLC patients who received platinum-based chemotherapy or chemoradiation (discovery phase). Significant SNPs were validated in an additional 278 advanced stage patients (validation phase). Cox proportional hazard regression analysis was used to evaluate the association of each SNP with OS. Results showed in chemotherapy only group the median survival time (MST) of NSCLC patients with RPA1: rs2270412 AA+GA genotype versus GG genotype was 10.5 versus 12.7 month [P = 0.004, hazard ratio (HR) = 1.42, 95% CI: 1.16-1.74, combined set]. The MST of patients with EXO1: rs9350 GA+AA genotype versus GG genotypes was 13.2 months versus 11.5 months (P = 0.009, HR = 0.70, 95% CI: 0.56-0.87, combined set). Patients harboring two unfavorable genotypes had a 2.02-fold increased risk of death (P = 3.16E-6) and chemoradiation would improve survival for them (HR = 0.75, 95% CI: 0.51-1.10, P = 0.27, combined set). The MST for patients with 0, 1, and 2 unfavorable genotypes was 13.2, 12.7 and 8.9 months, respectively (P = 0.0002, combined set). In summary, two variants in RPA1 and EXO1 were associated with poor survival in NSCLC patients treated by platinum-based chemotherapy. Adding radiotherapy could improve survival in patients harboring these risk genotypes.
authors.affiliation: Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.|Department of Epidemiology.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Epidemiology.
authors.forename: Jiang
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Thoracic/Head and Neck Med Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Epidemiology.
authors.forename: Xiang
authors.initials: X
authors.lastname: Shu
authors.affiliation: Department of Epidemiology.|The Fourth Military Medical University, XiAn 710032, China and.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Baohui
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Epidemiology.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Roth
authors.affiliation: Department of Epidemiology.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds