**Acknowledgements**

of severe emesis in patients was their heterozygous status at the rs1063045 locus. The protein encoded by *NBN* gene is an important component of the system repairing DNA double-strand breaks that can be induced by different environmental and endogenous agents, including cisplatin. The existing data suggest connections between polymorphic variants of the *NBN* gene

Intergroup comparison of genotypes generated with the microarrays revealed substantial differences in population frequencies of alleles and genotypes for many polymorphic markers. More than half of all markers differed significantly in the occurrence of their allelic variants

The proportion of significant genotype frequency differences resembled the results obtained in the first part of the study where a smaller number of polymorphic markers was involved (**Table 2**). Furthermore, the results of the comparisons of population-related associative spectra were also the same: there were no identical correlations for any of significant polymorphisms. All associations between the polymorphic markers and clinical outcomes were

These findings are generally compatible with the results of the HapMap project studying of the toxicity of platinum compounds (i.e., cisplatin and carboplatin) to lymphoblastoid cell lines from three groups of racially different individuals [19]. One can propose that the failure to detect common associations/commonly associated polymorphisms in our two groups was due to distinctive ethnic-related characteristics in the molecular mechanisms determining the sensitivity of patients to platinum drugs. Hence the difference in platinum drug sensitivity might not exclusively depend on the difference in variant frequencies of given polymorphisms. Another, but not exclusive, explanation of the findings could be a limitation of the number of polymorphisms tested and a possible omission of other potentially important markers. The latest may be mainly due to the misunderstanding of molecular phenotype(s) of the particular drug(s) [68]. The more relevant is the molecular phenotype, the higher is the potential to optimize the use of a particular drug. For some drugs, such as fluorouracil, irinotecan, and mercaptopurine, some relevant variants (i.e., *DPYD\*2A*, *DPYD* 2846T/A, and *TYMS* 2R/3R; *UGT1A1\*28* and *UGT1A1\*6*; *TPMT \*2, TPMT \*3A*, and *TPMT\*3C*) have been established but for other ones, including platinum-containing agents,

The importance of DNA repair, particularly nucleotide excision repair, for platinum cytotoxicity is widely accepted [64]. However, the overall contribution of even the most common genetic variants to predictions of response to platinum-based therapy is not yet well established [70, 71]. In principle, the situation with other "canonical" pathways affecting mainly cisplatin pharmacokinetics could be described the same way [72]. Therefore, the role of additional mechanisms that are not directly related to cisplatin cellular processing has also been proposed [73]. The results of our study overrepresented with the associations with polymorphisms in genes for different metabolic enzymes (*TPMT, NQO1, EPXH1,* etc.) supports the suggestion (the associations would remain significant even if they were adjusted with the Bonferroni method). The abundance of associations with genes involved in processing of

and the results of cisplatin-based chemotherapy [67].

in Russian and Yakut patients.

322 Ovarian Cancer - From Pathogenesis to Treatment

they are less apparent [68, 69].

specific for each of the ethnic group studied.

This study was supported by grants from the Programs "Fundamental Researches for Development of Biomedical Technologies" and "Molecular and Cell Biology" of the Russian Academy of Sciences and Russian Foundation for Basic Research.
