Mutagen sensitivity as a susceptibility marker for human hepatocellular carcinoma.
Although the pathogenesis of hepatocellular carcinoma (HCC) remains poorly understood, hepatitis B virus and dietary aflatoxin exposures are established etiological factors for this disease. We conducted a pilot study of 28 patients with HCC and 110 healthy controls matched for age, sex, and ethnicity to determine whether constitutional genetic instability, based on the quantification of mutagen-induced chromatid breaks in cultured lymphocytes, modifies an individual's risk of HCC development. The mean numbers of bleomycin-induced breaks per cell for cases and controls were 0.92 and 0.55, respectively (P < 0.0001). For benzo(a)pyrene diol epoxide (BPDE) sensitivity, the values were 0.90 for cases and 0.46 for controls (P < 0.0001). Nearly 68% of the cases but only 27% of the controls exhibited bleomycin sensitivity (i.e., had > or = 0.68 breaks per cell). Eighty % of the case group but only 22% of the control group exhibited BPDE sensitivity (i.e., had > or = 0.58 breaks per cell). On multivariate analyses, both bleomycin sensitivity and BPDE sensitivity were associated with significantly elevated risks for HCC, with odds ratios (95% confidence intervals) of 5.63 (2.30, 13.81) and 14.13 (3.52, 56.68), respectively. For individuals who were sensitive to both assays, the risk was 35.88. A synergistic interaction between the bleomycin sensitivity and BPDE sensitivity in HCC risk was suggested. These preliminary findings suggest that differences in host factors related to the predisposition to chromosome breakage, the capacity for DNA repair, or both may be involved in HCC development by influencing the predisposition of hepatitis B virus integration into human DNA or that the carcinogens induced DNA damage susceptibility. A larger study is needed to confirm these intriguing results.
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, and The University of Texas School of Public Health, Houston 77030, USA.
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Wu
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Gu
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Patt
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Hassan
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Spitz
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Beasley
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Hwang
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D016022:Case-Control Studies; D002842:Chromatids / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009152:Mutagenicity Tests; D009153:Mutagens; D010865:Pilot Projects
D000903:Antibiotics, Antineoplastic; D009153:Mutagens; D001761:Bleomycin; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide