High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation.

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Nunez MI, Behrens C, Woods DM, Lin H, Suraokar M, Kadara H, Hofstetter W, Kalhor N, Lee JJ, Franklin W, Stewart DJ, Wistuba II

High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation.

J Thorac Oncol. 2012 May;7(5):833-40. doi: 10.1097/JTO.0b013e31824de09c.

PubMed ID
22729036 [ View in PubMed
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Abstract

INTRODUCTION: Folate receptor alpha (FRalpha) and reduced folate carrier-1 (RFC1) regulate uptake of folate molecules inside the cell. FRalpha is a potential biomarker of tumors response to antifolate chemotherapy, and a target for therapies using humanized monocloncal antibody. Information on the protein expression of these receptors in non-small-cell lung carcinoma (NSCLC) is limited. MATERIAL AND METHODS: Expressions of FRalpha and RFC1 were examined by immunohistochemistry (IHC) in 320 surgically resected NSCLC (202 adenocarcinomas and 118 squamous cell carcinomas) tissue specimens and correlated with patients' clinico-pathologic characteristics. Folate receptor alpha gene (FOLR1) mRNA expression was examined using publicly available microarray datasets. FRalpha expression was correlated with thymidylate synthase and p53 expression in NSCLCs, and with epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten rat sarcoma viral (KRAS) gene mutations in adenocarcinomas. RESULTS: NSCLC overexpressed FRalpha and RFC1. In a multivariate analysis, lung adenocarcinomas were more likely to express FRalpha in the cytoplasm (OR = 4.39; p < 0.0001) and membrane (OR = 5.34; p < 0.0001) of malignant cells than squamous cell carcinomas. Tumors from never-smokers were more likely to express cytoplasmic (OR = 3.35; p<0.03) and membrane (OR = 3.60; p=0.0005) FRalpha than those from smokers. In adenocarcinoma, EGFR mutations correlated with higher expression of membrane FRalpha and FOLR1 gene expressions. High levels of FRalpha expression was detected in 42 NSCLC advanced metastatic tumor tissues. CONCLUSIONS: FRalpha and RFC1 proteins are overexpressed in NSCLC tumor tissues. The high levels of FRalpha in lung adenocarcinomas may be associated to these tumors' better responses to antifolate chemotherapy and represents a potential novel target for this tumor type.

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