Original Article Discovery of common SNPs in the miR-205/200 family-regulated epithelial to mesenchymal transition pathway and their association with risk for non-small cell lung cancer
Shuguang Leng, Amanda M. Bernauer, Rihong Zhai, Carmen S. Tellez, Li Su, Elizabeth A. Burki, Maria A. Picchi, Christine A. Stidley, Richard E. Crowell, David C. Christiani, Steven A. Belinsky
Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts; Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico; New Mexico VA Health Care System, Albuquerque, New Mexico; Department of Internal Medicine at University of New Mexico, Albuquerque, New Mexico; and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Received February 24, 2011; accepted March 23, 2011; Epub April 1, 2011; published May 15, 2011
Abstract: The activation of the epithelial-to-mesenchymal transition (EMT) program is an important step for tumor initiation, invasion, and metastasis in solid tumors, including lung cancer. The purpose of this study was to identify the sequence variants in the miR-205/200 family-regulated EMT pathway and test their association with risk for lung cancer. Fifty samples were resequenced to identify sequence variants in the miR-205/200 family-regulated EMT pathway. The association between tagSNPs and risk for non-small cell lung cancer was discovered and validated in New Mexico (386 cases and 514 controls) and Massachusetts (2453 cases and 1555 controls) case-control studies, respectively. The function of SNPs on miR-200b-a- 429 promoter activity was tested using luciferase reporter and expression assays. Forty-one sequence variants with minor allele frequency ≥ 0.03 were identified, and 16 variants were selected as tagSNPs. Genetic association analysis identified that the G allele of rs61768479 was associated with a 50% reduced risk for lung cancer (OR=0.50, 95%CI=0.300.85, uncorr-P=0. 01); however, this association was not validated (OR=0.90, 95%CI=0.721.13, uncorr-P=0.35). The G allele of rs61768479 was associated with lower promoter activity and miR expression by disrupting the binding of NKX2.5. In summary, no association was identified between sequence variants in the miR-205/200 family-regulated EMT pathway and risk for lung cancer. However, this study identified a comprehensive panel of tagSNPs (n=16) in the miR-205/200 family-regulated EMT pathway that can be applied to other EMT-related phenotypes such as cancer chemoresistence and prognosis. (IJMEG1102001).
Keywords: miR-200 family, miR-205, sequence variant, risk, lung cancer
Address all correspondence to: Steven A. Belinsky, PhD Lung Cancer Program Lovelace Respiratory Research Institute Albuquerque, New Mexico 87108 Phone: 505-348-9465; Fax: 505-348-4990 E-mail: firstname.lastname@example.org