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

• Published in: Clinical cancer research 2005-08, Vol.11 (16), p.5756-5763
• Main Authors: Holschneider, Christine H, Baldwin, Rae Lynn, Tumber, Kiran, Aoyama, Chisa, Karlan, Beth Y
• Format: Article
• Language: English
• Subjects: Acid Anhydride Hydrolases - analysis; Acid Anhydride Hydrolases - genetics; Adult; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Environmental carcinogenesis/toxicology; Female; Gene Deletion; Gynecological cancers: cervical; Homozygote; Humans; Immunohistochemistry; LOH and marker studies; Microsatellite Repeats; Middle Aged; Neoplasm Proteins - analysis; Neoplasm Proteins - genetics; Neoplasm Staging; Polymerase Chain Reaction - methods; Smoking - adverse effects; Tobacco; Uterine Cervical Neoplasms - etiology; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0234

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.