Genetic Variations Associated with Postoperative Recurrence in Stage I Non–Small Cell Lung Cancer

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 = 2.81; P = 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 = 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. ©2014 AACR.

[1]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[2]  E. Letouzé,et al.  SNP array profiling of childhood adrenocortical tumors reveals distinct pathways of tumorigenesis and highlights candidate driver genes. , 2012, The Journal of clinical endocrinology and metabolism.

[3]  J. Yokota,et al.  Identification of CpG islands hypermethylated in human lung cancer by the arbitrarily primed-PCR method , 1998, Human Genetics.

[4]  N. Carter,et al.  Array Comparative Genomic Hybridization Analysis of Colorectal Cancer Cell Lines and Primary Carcinomas , 2004, Cancer Research.

[5]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[6]  P. Pairolero,et al.  Survival after recurrent nonsmall-cell lung cancer after complete pulmonary resection. , 2007, The Annals of thoracic surgery.

[7]  Andrew P Morris,et al.  Basic statistical analysis in genetic case-control studies , 2011, Nature Protocols.

[8]  Farin Kamangar,et al.  Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  T. Marugame,et al.  Comparison of time trends in lung cancer mortality (1990-2006) in the world, from the WHO Mortality Database. , 2009, Japanese journal of clinical oncology.

[10]  L. Appel,et al.  Projected mortality from lung cancer in South Korea, 1980-2004. , 1998, International journal of epidemiology.

[11]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[12]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[13]  J. Crowley,et al.  The IASLC Lung Cancer Staging Project: Proposals for the Revision of the TNM Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[14]  Peter Kraft,et al.  A Genome-Wide Association Study of Prognosis in Breast Cancer , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[15]  M Schemper,et al.  A note on quantifying follow-up in studies of failure time. , 1996, Controlled clinical trials.

[16]  Yasunori Sato,et al.  Genome-Wide Association Study on Overall Survival of Advanced Non-small Cell Lung Cancer Patients Treated with Carboplatin and Paclitaxel , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[17]  J. Roh,et al.  Changing trends in histologic types of lung cancer during the last decade (1981-1990) in Korea: a hospital-based study. , 1994, Lung cancer.

[18]  J. Crowley,et al.  The IASLC Lung Cancer Staging Project: Validation of the Proposals for Revision of the T, N, and M Descriptors and Consequent Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[19]  T. Manabe,et al.  Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients , 2004, British Journal of Cancer.

[20]  Zhen Su,et al.  Integrative genomic analyses reveal clinically relevant long non-coding RNA in human cancer , 2013 .

[21]  David C Christiani,et al.  Genome-wide analysis of survival in early-stage non-small-cell lung cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Yusuke Nakamura,et al.  A Genome-Wide Association Study of Overall Survival in Pancreatic Cancer Patients Treated with Gemcitabine in CALGB 80303 , 2011, Clinical Cancer Research.

[23]  Jian Gu,et al.  Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy. , 2011, Journal of the National Cancer Institute.

[24]  Wen Tan,et al.  Genome-Wide Association Study of Prognosis in Advanced Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy , 2012, Clinical Cancer Research.

[25]  Michael Thomas,et al.  Genome-wide screening for prognosis-predicting genes in early-stage non-small-cell lung cancer. , 2004, Lung cancer.

[26]  S. Gabriel,et al.  Pan-cancer patterns of somatic copy-number alteration , 2013, Nature Genetics.

[27]  H. Wada,et al.  Clinical significance of caspase‐3 expression in pathologic‐stage I, nonsmall‐cell lung cancer , 2001, International journal of cancer.

[28]  W. Hsu,et al.  Post-recurrence survival in completely resected stage I non-small cell lung cancer with local recurrence , 2009, Thorax.

[29]  Peter Donnelly,et al.  A comparison of bayesian methods for haplotype reconstruction from population genotype data. , 2003, American journal of human genetics.

[30]  H. Yum,et al.  National Survey of Lung Cancer in Korea, 2005 , 2007 .