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The Hepatocyte Nuclear Factor 3 Gene, HNF3 (FOXA1), on Chromosome Band 14q13 Is Amplified and Overexpressed in Esophageal and Lung Adenocarcinomas¹

Section of General Thoracic Surgery, Departments of Surgery [L. L., C. T. M., J. I. C., M. S. P., J. Y., M. B. O., D. G. B.], Human Genetics [S. L. D., T. W. G.], Pathology [R. W.], and Pediatrics [D. E. M., S. M. H., T. W. G.], University of Michigan Medical School, Ann Arbor, Michigan 48109

Genomic amplification is observed in many, if not all, types of human malignancy and is one of the mechanisms for the activation of dominant-acting oncogenes in tumorigenesis. In the present study, three amplified restriction fragments were identified in an esophageal adenocarcinoma (P16) using the restriction landmark genome scanning two-dimensional gel technique. These fragments were cloned, sequenced, and mapped to chromosome band 14q13. Using the sequence tagged site-amplification mapping approach, we defined the core-amplified domain by screening 75 normal-tumor paired esophageal samples. The frequency of 14q13 amplification is 6.7% in esophageal tumors, and the amplicon spans >6 Mb in 1 tumor but is contained in a region <0.3 Mb in all of the remaining amplified tumors. Quantitative reverse transcription-PCR (RT-PCR) of 8 genes and expressed sequence tags located within the core-amplified domain revealed that the HNF3 (FOXA1)⁴ gene, a forkhead gene family member, was overexpressed in all of the amplified esophageal tumors. HNF3 amplification was confirmed by Southern blot and interphase fluorescence in situ hybridization analyses, and the results of real-time RT-PCR were consistent with that of the regular quantitative RT-PCR. Increased immunohistochemical nuclear staining of the HNF3 protein was detected in all of the tumors containing 14q13 amplification. Affymetrix oligonucleotide microarrays of 86 lung adenocarcinomas demonstrated that expression of the HNF3 mRNA was elevated (2.5-fold of mean expression in normal lung) in 37% (32 of 86) of the tumors analyzed. Gene amplification of HNF3 was detected in 2 of the 5 overexpressed lung tumors examined. This is the first report of HNF3 amplification, and overexpression in esophageal and lung adenocarcinomas. Amplification of HNF3 in esophageal and lung tumors may suggest a potential oncogenic role for this gene in tumorigenesis.

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