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The Fragile Histidine Triad Gene: A Molecular Link Between Cigarette Smoking and Cervical Cancer

Authors' Affiliations: ¹ Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, ² Women's Cancer Research Institute, Cedars-Sinai Medical Center, Los Angeles; Departments of ³ Obstetrics and Gynecology and ⁴ Pathology, Olive View-UCLA Medical Center, Sylmar, California

Requests for reprints: Christine H. Holschneider, Gynecologic Oncology, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS 24-127, Los Angeles, CA 90095-1740. E-mail: Christine.Holschneider{at}cshs.org.

Purpose: Smoking is an epidemiologic risk factor for cervical cancer. The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered in 80% of tobacco-associated lung cancers. We hypothesized that reduced FHIT protein expression, homozygous deletions (HD) or hemizygous deletions (HemiD) and microsatellite alterations (MA) at the FHIT/FRA3B locus occur more commonly in cervical cancers of smokers than nonsmokers.

Experimental Design: Archival tissues of 58 patients with stage IA1 to IB2 squamous cell carcinoma of the cervix were identified. FHIT protein expression was studied with immunohistochemistry. Laser capture microdissection was used to isolate tumor and normal DNA. HD/HemiD of FHIT exons 4 and 5 were analyzed by monoplex real-time PCR. MA at FHIT/FRA3B were studied with multiplex nested PCR with three fluorescently labeled microsatellite markers (D3S1300, D3S1312, and D3S1480).

Results: Eighteen of 26 tumors from smokers (69%) and 13 of 32 nonsmokers (41%; P < 0.05) showed loss of FHIT protein expression. Thirty-seven stage IB tumors yielded sufficient DNA for analyses. HD or HemiD of both exons tested occurred in 8 of 17 smokers (47%) and 2 of 20 nonsmokers (10%; P < 0.05). MA at more than two sites were found in 11 of 17 tumors of smokers (65%) and 6 of 20 nonsmokers (30%; P < 0.05). Mean composite genomic FHIT alteration scores were significantly higher for tumors of smokers versus nonsmokers (0.67 versus 0.40; P < 0.02).

Conclusion: Loss of FHIT expression, HD, HemiD, and MA at the FHIT/FRA3B locus occur significantly more commonly in cervical cancers of smokers. These findings suggest that the tumor suppressor gene FHIT may represent a molecular target in cigarette smoking–associated cervical carcinogenesis.

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