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Structure and Expression of the Human FHIT Gene in Normal and Tumor Cells¹

Departments of Microbiology and Immunology [T. D., P. H., T-B. F., M. O., Z. S., R. B., M. N., K. K., M. L. V., M. G. C., H. I., C. M. C., K. H.], Otolaryngology [D. R., J. R.], and Surgical Pathology [P. M.], Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107

The FHIT gene, encoded by 10 exons in a 1.1-kb transcript, encompasses approximately 1 Mb of genomic DNA, which includes the hereditary RCC t(3;8) translocation break at 3p14.2, the FRA3B common fragile region, and homozygous deletions in various cancer-derived cell lines. Because some of these genetic landmarks (e.g., the t(3;8) break between untranslated FHIT exons 3 and 4, a major fragile region that includes a viral integration site between exons 4 and 5, and cancer cell homozygous deletions in intron 5) do not necessarily affect coding exons and yet apparently affect expression of the gene product, we examined the FHIT locus and its expression in detail in more than 10 tumor-derived cell lines to clarify mechanisms underlying aberrant expression. We observed some cell lines with apparently continuous large homozygous deletions, which included one or more coding exons; cell lines with discontinuous deletions, some of which included or excluded coding exons; and cell lines that exhibited heterozygous and/or homozygous deletions, by Southern blot analysis for the presence of specific exons. Most of the cell lines that exhibited genomic alterations showed alteration of FHIT transcripts and absence or diminution of Fhit protein.

¹ This work was supported by United States Public Health Service Grants CA51083, CA21124, and CA39860. Kimmel Cancer Center Core Grant CA56336, and a gift from R. R. M. Carpenter III and Mary K. Carpenter.

² Present address: Department of Genetics and Pathology, Medical Academy, Al. Powstancow Wlkp. 72, 70–111 Szczecin, Poland.

³ Present address: Banyu Tsukuba Research Institute, Okubo 3, Tsukuba 300-33 Japan. Phone: 011-81-298-77-2000; Fax: 011-81-298-77-2024.

⁴ To whom requests for reprints should be addressed, at Kimmel Cancer Institute, BLSB, Room 1008, 233 South 10th Street, Philadelphia, PA 19107. Phone: (215) 503-4656; Fax: (215) 923-4498.

Received 10/ 7/96. Accepted 12/19/96.

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