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Analysis of the FHIT Gene and FRA3B Region in Sporadic Breast Cancer, Preneoplastic Lesions, and Familial Breast Cancer Probands¹

Hamon Center for Therapeutic Oncology Research [M. A., I. I. W., K. M. F., C. B., D. R. K., G. E. T., J. D. M., A. F. G.] and Departments of Internal Medicine [J. D. M.], Pediatrics [G. E. T.], Pharmacology [J. D. M.], Cell Biology [J. S.], and Pathology [M. H. S., A. F. G.], University of Texas Southwestern Medical Center, Dallas, Texas 75235-8593; Department of Pathology, Pontificia Universidad Catolica de Chile, Santiago, Chile [I. I. W.]; and Texas Oncology, P. A., Dallas, Texas 75246 [J. B.]

The FHIT gene, which spans the FRA3B fragile site at chromosome 3p14.2, is a candidate tumor suppressor gene in breast and other cancers. We investigated FHIT and FRA3B for loss of heterozygosity (LOH); homozygous deletions; abnormal transcripts; and acquired/germ-line point mutations in breast cancer cell lines (n = 32), breast epithelial and stromal cell cultures (n = 18), microdissected invasive (n = 16) and ductal in situ carcinomas (n = 6), and their accompanying normal and abnormal epithelial foci (n = 14). LOH at 3p14.2, especially at FHIT intragenic marker D3S1300, was found in 6 of 16 microdissected invasive tumors and 3 of 6 ductal in situ carcinomas. In accompanying preneoplastic foci, LOH occurred in two of eight intraductal hyperplasias but not in histologically normal ductal epithelium (n = 6). Three of 32 (9%) breast cancer cell lines demonstrated homozygous deletions of FHIT exon 4 (two cases) and exon 5 (one case), which correlated with exon 4-deleted transcripts and loss of the cDNA transcript containing the coding exons 5–9, respectively. Normal mammary cultures and 31 of 32 tumor cell lines (97%) expressed wild-type coding transcripts as well as a minor exon 8-deleted message. Single-strand conformation polymorphism analysis of the coding exons in the 32 tumor and 18 normal breast cell lines and their sequencing revealed four silent polymorphisms and a germ-line histidine triad point mutation (651 GT) in a tumor arising in a 70-year-old woman. This mutation was also present in one of her two thus far unaffected daughters. Analysis of additional DNAs from 280 probands of high-risk breast cancer families for other FHIT exon 8 mutations detected an intronic point mutation 13 bases upstream of exon 8. Thus, we have demonstrated relatively early abnormalities of the FHIT/FRA3B region in breast cancer and discovered two rare FHIT germ-line mutations. The expression of a transcript containing the coding exons in nearly all cell lines, including those with germ-line mutations, suggests the possibility that another gene in the FRA3B region may be involved in the pathogenesis of breast cancer.

¹ This work was supported in part by United States Army Research Grant DAMD17-94-J-4077 and by grants from the G. Harold and Leila Y. Mathers Charitable Foundation and the Susan G. Komen Foundation. M. A. was supported by National Service Award 1-T32-CA66817-01A1 from the National Cancer Institute, K. F. was supported by an American Society of Clinical Oncology Young Investigator Award, and G. T. was supported by NIH Grant CA-70472.

² To whom requests for reprints should be addressed, at Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Building NB, Room 106, 5323 Harry Boulevard, Dallas, TX 75235-8593. Phone: (214) 648-4900; Fax: (214) 648-4940; E-mail: gazdar@simmons.swmed.edu.

Received 4/11/97. Accepted 7/17/97.

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