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A SNP in a let-7 microRNA Complementary Site in the KRAS 3' Untranslated Region Increases Non–Small Cell Lung Cancer Risk

Departments of ¹ Molecular, Cellular and Developmental Biology, ² Therapeutic Radiology, ³ Genetics, ⁴ Pathology, and ⁵ Epidemiology, Yale University, New Haven, Connecticut; and ⁶ Department of Environmental Health, Harvard School of Public Health and ⁷ Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts; and ⁸ Department of Internal Medicine, University of New Mexico and ⁹ Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico

Requests for reprints: Joanne B. Weidhaas and Frank J. Slack, Yale University, 333 Cedar Street, New Haven, CT 06520. Phone: 203-737-4267; Fax: 203-785-6309; E-mail: joanne.weidhaas{at}yale.edu and frank.slack{at}yale.edu.

Key Words: KRAS • let-7 • microRNA binding site SNP

Lung cancer is the leading cause of cancer deaths worldwide, yet few genetic markers of lung cancer risk useful for screening exist. The let-7 family-of-microRNAs (miRNA) are global genetic regulators important in controlling lung cancer oncogene expression by binding to the 3' untranslated regions of their target mRNAs. The purpose of this study was to identify single nucleotide polymorphisms (SNP) that could modify let-7 binding and to assess the effect of such SNPs on target gene regulation and risk for non–small cell lung cancer (NSCLC). let-7 complementary sites (LCS) were sequenced in the KRAS 3' untranslated region from 74 NSCLC cases to identify mutations and SNPs that correlated with NSCLC. The allele frequency of a previously unidentified SNP at LCS6 was characterized in 2,433 people (representing 46 human populations). The frequency of the variant allele is 18.1% to 20.3% in NSCLC patients and 5.8% in world populations. The association between the SNP and the risk for NSCLC was defined in two independent case-control studies. A case-control study of lung cancer from New Mexico showed a 2.3-fold increased risk (confidence interval, 1.1–4.6; P = 0.02) for NSCLC cancer in patients who smoked <40 pack-years. This association was validated in a second independent case-control study. Functionally, the variant allele results in KRAS overexpression in vitro. The LCS6 variant allele in a KRAS miRANA complementary site is significantly associated with increased risk for NSCLC among moderate smokers and represents a new paradigm for let-7 miRNAs in lung cancer susceptibility. [Cancer Res 2008;68(20):8535–40]

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