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FHIT and FRA3B 3p14.2 Allele Loss Are Common in Lung Cancer and Preneoplastic Bronchial Lesions and Are Associated with Cancer-related FHIT cDNA Splicing Aberrations¹

Hamon Center for Therapeutic Oncology Research and Departments of Internal Medicine, Pharmacology, and Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8593 [K. M. F., E. J. B., A. V., I. W., Y. S., S. A. B., M. A., A. F. G., J. D. M.]; Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois [S. T. O., F. V. R.]; The Prince Charles Hospital, Brisbane, Australia [P. V. Z.]; and Department of Oncology, Free University Hospital, Amsterdam, the Netherlands [G. G.]

We evaluated primary lung cancers, tumor cell lines, and preneoplastic bronchial lesions for molecular genetic abnormalities in the candidate tumor suppressor gene FHIT, which spans the FRA3B fragile site at 3p14.2. 3p14.2 allele loss was very frequent in 32 lung cancer cell lines [100% of small cell lung cancer and 88% of non-small cell lung cancer (NSCLC)] and 108 primary NSCLC cancers (45%), with numerous breakpoints indicating involvement of several distinct regions in the FRA3B site. 3p14 allele loss was least frequent in the adenocarcinoma subtype and occurred at the relatively late carcinoma in situ stage of preneoplastic bronchial lesions found in NSCLC patients. Homozygous deletions within the FHIT/FRA3B region were found in 6 of 135 (4.4%) thoracic cancer cell lines. Northern blot showed low or absent FHIT expression in most thoracic cancer cell lines tested, whereas reverse transcription-PCR showed that 59–62% exhibited aberrant FHIT transcripts but nearly always (93–100%) also expressing the wild-type transcripts. Aberrant transcripts included precise deletions of FHIT exons, insertion of non-FHIT sequences between exons and insertions replacing exons. Complete open reading frame single-strand conformational poly-morphism analysis of 102 lung cancer cDNAs revealed only one nonsplicing mutation. Normal cells including bronchial epithelium, lung, and trachea expressed wild-type FHIT transcript and a variant transcript deleted for exon 8 but not the other aberrant transcripts, arguing against exon 8-deleted FHIT transcripts being tumor specific. Our findings support the conclusion that FHIT/FRA3B abnormalities are associated with lung cancer pathogenesis but that FHIT abnormalities differ from the types of mutations and lack of wild-type transcript found in classic tumor suppressor genes, and functional studies are needed to define the role of FHIT in thoracic tumorigenesis.

¹ This work was supported in part by grants from the G. Harold and Leila Y. Mathers Charitable Foundation (to J. D. M.), National Cancer Institute Lung Cancer SPORE Grant P50 CA 70907 (to J. D. M.), The Malouf Found (to J. D. M.), and a State of Texas Advanced Research Program grant (to J. D. M.). K. F. was supported by an ASCO Young Investigator Award, M. A. by National Cancer Institute 1-T32-CA66817-01A1, and E. J. B. by the University of Texas Southwestern Graduate Program in Cell Regulation.

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

Received 12/13/96. Accepted 4/17/97.

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