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Some epidemiological evidences suggest that women are at a relatively higher risk of lung cancer than men for a given degree of smoking. The reasons why women may be more susceptible to tobacco than men are not well understood. It is possible that risk increases because of increasing in endogenous sex steroid exposure. Catechol metabolites of estradiol are associated with high risk of carcinogenesis. Inactivation of these catechol metabolites by O-methylation is catalyzed by Catechol-O-Methyltransferase (COMT). Low COMT activity, resulting in higher concentration of catechol estrogens, might be related to an increased carcinogenic burden. In a case series study, we evaluated the association of COMT low activity allele (COMTMET) and serum estradiol and progesterone levels in 116 male and 56 female lung cancer patients. The mean serum estradiol levels in male lung cancer patients were 28.6, 29.4 and 33.8 (pg/ml) for COMT val/val, val/met and met/met genotypes respectively (p-for-trend = 0.04). The mean serum estradiol levels in female lung cancer patients were 31.3, 39.0 and 79.0 for COMT val/val, val/met and met/met genotypes respectively (p-for-trend = 0.50). COMTMET allele was significantly associated with an increased risk of high serum estradiol level (defined as > 28.8 pg/ml) in male lung cancer patients with adjusted OR (95% CI) of 2.0 (0.5, 7.7), 7.6 (1.9, 30.3) for COMT val/met and met/met genotypes respectively, adjusted for age, race, body mess index and pack-years. The association of COMTMET allele and the risk of high serum estradiol level was not significant in female lung cancer patients. The mean serum progesterone levels in male lung cancer patients were 1.0, 1.7 and 2.3 (pg/ml) for COMT val/val, val/met and met/met genotypes respectively (p-for-trend = 0.01). The mean serum progesterone levels in female lung cancer patients were 1.5, 2.7 and 1.2 for COMT val/val, val/met and met/met genotypes respectively (p-for-trend = 0.60). COMTMET allele was significantly associated with an increased risk of high serum progesterone level (defined as > 0.83 pg/ml) in male lung cancer patients with adjusted OR (95% CI) of 2.7 (0.9, 8.2), 3.4 (1.1, 11.4) for COMT val/met and met/met genotypes respectively. The association of COMTMET allele and risk of high serum progesterone level was not significant in female lung cancer patients. Our preliminary results suggested that COMTMET allele is significantly associated with increased serum estradiol and progesterone levels in male lung cancer patients. We hypothesize that COMT V158M polymorphism modulates lung cancer risk by affecting the life time exposure to sex steroids and the risk modulation by COMT may be different between males and females. We are currently testing this hypothesis using an on-going lung cancer case-control study in the Baltimore metropolitan area.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]