Hypoxia pathway genetic variants predict survival of non-small-cell lung cancer patients receiving platinum-based chemotherapy

<span class="paragraphSection"><div class="boxTitle">Abstract</div>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 <span style="font-style:italic;">RPA1</span>: rs2270412 AA+GA genotype versus GG genotype was 10.5 versus 12.7 month [<span style="font-style:italic;">P =</span> 0.004, hazard ratio (HR) = 1.42, 95% CI: 1.16–1.74, combined set]. The MST of patients with <span style="font-style:italic;">EXO1</span>: rs9350 GA+AA genotype versus GG genotypes was 13.2 months versus 11.5 months (<span style="font-style:italic;">P</span> = 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 (<span style="font-style:italic;">P</span> = 3.16E−6) and chemoradiation would improve survival for them (HR = 0.75, 95% CI: 0.51–1.10, <span style="font-style:italic;">P</span> = 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 (<span style="font-style:italic;">P</span> = 0.0002, combined set). In summary, two variants in <span style="font-style:italic;">RPA1</span> and <span style="font-style:italic;">EXO1</span> were associated with poor survival in NSCLC patients treated by platinum-based chemotherapy. Adding radiotherapy could improve survival in patients harboring these risk genotypes.</span>

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