Distinct prevalence of CYP19 del3(TTTA)7 allele in premenopausal versus postmenopausal breast cancer patients

K.P. Hansona, PhD MD, E.N. Suspitsina, MD, MY Grigorieva, MD, A.V. Togoa, PhD, ES Kuliginaa, PhD, E.V. Belogubovaa, PhD, K.M. Pozharisskia, PhD MD, Oleg L. Chagunavab, PhD MD, E.P. Sokolovc, PhD, C. Theilletd, PhD, L.M. Bersteina, PhD MD, E.N. Imyanitova, PhD MD

a N.N. Petrov Institute of Oncology, St.-Petersburg, Russia; b Oleg L. Chagunava, Center of Mammology, St.-Petersburg, Russia; c Evgeny P. Sokolov, Institute of Zoology, St.-Petersburg, Russia; d Charles Theillet, Centre de Recherche en Cancerologie, Montpellier, France.

AIMS: CYP19 gene encodes for the enzyme called aromatase, which plays a key role in conversion of androgens to estrogens. CYP19 intron 4 (TTTA)n polymorphism has been reported to be associated with breast cancer (BC) risk, although conflicting evidence were published as well. This study was aimed to clarify the role of CYP19 polymorphism in breast cancer susceptibility. METHODS: Here we employed non-traditional, highly demonstrative design of the molecular epidemiological study, where the comparison of BC cases and healthy middle-aged female donors was supplemented by the analysis of the groups with extreme characteristics of either BC risk (bilateral breast cancer (biBC) patients) or cancer tolerance (tumor-free elderly women aged ³ 75 years). RESULTS: None of the (TTTA)n polymorphic variants was overrepresented among the affected women as compared to any of the control groups. However, the 3 bp deletion/insertion CYP19 polymorphism, which is located in the same intron approximately 50 bp upstream to the (TTTA)n repeat, was evidently associated with the menopausal status in both BC and biBC cohorts. In particular, the del3(TTTA)7 allele occurred significantly more frequently in premenopausal than in postmenopausal BC patients (65/172 (37.8%) vs. 67/310 (21.6%); P = 0.0001; OR = 2.20 (1.46 3.32)), while the perimenopausal cases demonstrated an intermediate value (9/34 (26.5%)). In the biBC cohort, women who developed both tumors in premenopausal period had significantly higher prevalence of the del3(TTTA)7 than the patients with postmenopausal onset of the bilateral disease (16/46 (34.8%) vs. 8/50 (16.0%); P = 0.035; OR = 2.80 (1.08 7.23)); those biBC patients, whose tumors diagnoses were separated by the cessation of menses, displayed intermediate occurrence of the del3(TTTA)7 allele (7/32 (21.9%)). CONCLUSION: The del3(TTTA)7 allele appears to be related with the increased risk of premenopausal breast cancer but may protect against the postmenopausal disease. Similar tendencies in the del3(TTTA)7 allele distribution in BC and biBC patients suggest that its association with the menopausal status of the patients is truly non-random and thus deserves further detailed investigation.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Risk Assessment, Part 1.