Imaging, Diagnosis, Prognosis Genetic Variations Associated with Postoperative Recurrence in Stage I Non–Small Cell Lung Cancer Kyong-Ah Yoon, Mee Kyung Jung, Donghoon Lee, Kieun Bae, Jung Nam Joo, Geon Kook Lee, Hyun-Sung Lee, and Jin Soo Lee Abstract Purpose: Postoperative recurrence in stage I non–small cell lung cancer (NSCLC) is the major cause of a poor prognosis. This study aims to identify genetic variants that are associated with the prognosis of early- stage NSCLCs. Experimental Design: A genome-wide association study (GWAS) was conducted in 250 patients in stage I NSCLCs and the results were replicated in additional 308 patients. Results: Results from an Affymetrix Genome-wide Human SNP array in 250 patients identified 94 SNPs with significant associations (P < 2  10 4 ), which were selected for replication in 308 additional patients. Pooled analysis of the 558 patients determined that rs1454694 in chromosome 4q34 was the most significant marker of lung cancer prognosis in the stage I patients (adjusted HR ¼ 2.81; P ¼ 5.91  10 8 ). After the candidate loci were mapped, an additional four markers at chromosome 4q34.3 were significantly associated with recurrence-free survival (RFS; P < 5  10 5 ). A haplotype of five SNPs in 4q34 also showed significant association with RFS (P ¼ 4.29  10 6 ). Conclusions: A genetic polymorphism rs1454694 was identified as a novel genetic risk factor for RFS of stage I NSCLCs. This genome-wide study suggests that genetic markers in 4q34.3 contribute to predict the prognosis of Korean patients with stage I NSCLCs. Clin Cancer Res; 20(12); 3272–9. Ó2014 AACR. Introduction Lung cancer is the leading cause of cancer mortality world- wide (1–3). In Korea, non–small cell lung cancer (NSCLC) constitutes the majority of all diagnosed lung cancers with 70% of patients with NSCLCs being diagnosed at stages III and IV and only 17% at stage I (4, 5). The overall survival (OS) of patients with advanced NSCLCs remains poor, whereas the survival time in early-stage patients has improved. Of those patients in pathologic stage IA and IB NSCLCs who are candidates for surgical resection, the 5-year OS rates are approximately 73% and 58%, respectively (6, 7). While postoperative adjuvant chemotherapy is the standard care among patients with stage II to IIIA NSCLCs who have undergone complete resections, surgery remains the only recommended guideline for the treatment of stage I NSCLCs. The recurrence rate in stage I patients who under- went surgical resection ranges from 13% to 41% (8, 9). Thus, postoperative recurrence is a major obstacle to prolonged survival in early-stage NSCLCs, and consider- able differences exist among patients with the same path- ologic stage. Genetic markers that could identify those at high risk for recurrence are essential for the development of an effective clinical practice strategy, as patients with a poor prognosis could undergo more aggressive treatment regimens. Genome-wide association studies (GWAS) identify phe- notype-correlated markers that are based on tagging poly- morphisms across the entire genome. GWAS were used to identify not only as the susceptibility markers but also as predictors of clinical outcome in cancers of the breast, pancreas, and lung (10–13). Several genome-wide studies reported genetic polymorphisms associated with lung can- cer prognosis. Huang and colleagues reported 5 SNPs in the STK39, PCDH7, A2BP1, and EYA2 genes were associated with OS in early-stage NSCLCs from GWAS with tumor tissues (14). An SNP located in the chemokine-like receptor 1 gene (12q23.3) was associated with OS of patients with advanced-stage NSCLCs receiving platinum-based chemo- therapy (15). Another GWAS identified 3 prognostic mar- kers associated with OS for advanced NSCLCs treated with carboplatin and paclitaxel (16). However, genetic poly- morphisms associated with the risk for postoperative recur- rence in completely resected stage I patients with NSCLCs have not been identified. In this study, we conducted genome-wide screening and a subsequent replication study involving 558 stage I patients Authors' Affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Authors: Jin Soo Lee Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi, 410-769, Korea. Phone: 82-31-920-1510; Fax: 82-31-920-1520; E-mail: jslee@ncc.re.kr; and Hyun-Sung Lee, hyunsungleethoracic@gmail.com doi: 10.1158/1078-0432.CCR-13-2835 Ó2014 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 20(12) June 15, 2014 3272 on April 28, 2017. © 2014 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst April 15, 2014; DOI: 10.1158/1078-0432.CCR-13-2835