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Background  Ovarian malignancies are often diagnosed in advanced stage and at the same time resistance to treatment, both intrinsic and developed during treatment, is sometimes observed. These facts underscore the need for new markers of ovarian cancer risk, as well as markers of treatment effectiveness.    Methods  In this study we genotyped 225 ovarian cancer patients, 64 breast and ovarian cancer patients and 348 healthy controls. In total, 12 polymorphic variants and 2 deletions in  PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53  and  ATP7B  genes were analyzed using ASA-PCR, RFLP-PCR, multiplex-PCR and sequencing.    Results  Ten genetic polymorphisms were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. Impact of  PGR  gene polymorphisms on ovarian cancer risk was specific only for the group of the  BRCA1  mutation carriers (in presence of p.Val660Leu variant- OR 2,82; p = 0,010), which confirms the difference in modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of  ATP7B  gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in all groups excluding the group with  BRCA1  mutation. Cumulative risk analysis revealed 3 unfavorable variants that increased significantly the risk of developing ovarian cancer (p.Ile1145 =  ABCB1 + p.Asp1853Asn  ATM + p.Ser406Ala  ATP7B - OR 7,47; p = 0,002) and significantly modified the progression free survival (PFS) of the patients, and also two favorable genotypes which protected against ovarian cancer (p.Arg952Lys  ATP7 B+ p.Arg72Pro TP53- OR 0,50; p = 0,008). PFS analysis for carriers of favorable versus unfavorable genotypes emphasized the impact of the regulation of cell cycle (p.Asp1853Asn  ATM ) and active transport of xenobiotics (p.Ser894Ala/Thr  ABCB1 ) on the risk of disease progression (HR 3,81; p = 0,010) after paclitaxel/cisplatin chemotherapy.    Conclusions  The unfavorable genetic variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors.

Genetic polymorphisms and gene-dosage effect in ovarian cancer risk and response to paclitaxel/cisplatin chemotherapy