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A few founder BRCA1 mutations (5382insC 4154delA 185delAG) account for up to 15% of high-risk (young-onset or familial or bilateral) breast cancer (BC) cases in Russia The impact of non founder BRCA1 mutations in this country is less studied in particular there are no reports analyzing gross rearrangements of this gene in the Russian patient series We selected for the study 95 founder mutation negative high-risk BC cases Combination of high-resolution melting (HRM) and sequencing revealed six presumably BC-associated alleles (2080delA, 4808C > G 5214C > T 5236G > A 5460G > T 5622C > T) and one variant of an unknown significance (4885G > A) The pathogenic role of the 5236G > A mutation leading to G1 706E substitution was further confirmed by the loss of heterozygosity analysis of the corresponding tumor tissue Multiplex ligation-dependent probe amplification (MLPA) revealed two additional BRCA1 heterozygotes which carried BRCA1 deletions involving exons 1-2 and 3-7 respectively Based on the results of this investigation and the review of prior Russian studies three BRCA1 mutations (2080delA 3819de15 3875del4) were considered with respect to their possible founder effect and tested in the additional series of 210 high-risk BC patients two BACA heterozygotes (2080delA and 3819de15) were revealed We conclude that the non-founder mutations constitute the minority of BRCA1 defects in Russia (C) 2010 Elsevier Ireland Ltd All rights reserved

BRCA1 5382insC variant was repeatedly detected in Jewish breast cancer (BC) families residing in USA and Israel as well as in non-Jewish familial BC patients from Poland, Latvia, Hungary, Russia and some other European countries. However, the distribution of BRCA1 5382insC mutation in unselected BC cases vs. controls has been systematically investigated mainly in Ashkenazi Jews. Here we applied a case-control study design in order to evaluate the impact of BRCA1 5382insC allele on BC incidence in St Petersburg, Russia. High frequency of the BRCA1 5382insC allele was detected in a group of bilateral breast cancer patients (10.4%; 15/144). Randomly selected unilateral BC cases demonstrated noticeable occurrence of BRCA1 5382insC mutation as well (3.7%; 32/857), with evident excess of the carriers in the early-onset (40 years) category (6.1%; 6/99) and in patients reporting breast and/or ovarian tumours in first-degree relatives (11.3%; 11/97). Strikingly, none of 478 middle-aged controls and 344 elderly tumour-free women carried the 5382insC variant. The presented data confirm a noticeable contribution of BRCA1 5382insC mutation in BC development in Russia, that may justify an extended BRCA1 5382insC testing within this population.

This study was aimed to assess the role of CHEK2 1100delC mutation in breast cancer (BC) predisposition in Russia. The 1100delC allele was detected in 14/660 (2.1%) unilateral BC cases and in 8/155 (5.2%) patients with the bilateral form of the disease, but only in 1/448 (0.2%) middle-aged control females and in none of 373 elderly tumor-free women. The obtained data point at potentially high clinical relevance of CHEK2 1100delC testing in females of Russian origin and warrant similar case-control studies in ethnically and geographically related regions, especially in Ukraine, Belarus and Baltic countries.

The gene for Nijmegen chromosomal breakage syndrome (NBS1) plays a role in a variety of processes protecting chromosomal stability. Recently, it was suggested in a Polish case-control study that the founder hypomorphic mutation in NBS1, 657del5, which occurs in approximately 0.5% of Slavic subjects, may be associated with an increased risk of breast cancer (BC). We attempted to validate these findings in Russian subjects, who are also of Slavic descent. Heterozygous carriers for the 657del5 mutation were detected in 2 of 173 (1.16%) bilateral breast cancer cases, 5 of 700 (0.71%) unilateral breast cancer patients, 2 of 348 (0.57%) healthy middle-aged females and in 0 of 344 elderly tumor-free women. The difference between the “extreme” cohorts, i.e., biBC patients vs. elderly controls, approached the formal limit of statistic significance (p = 0.046). LOH at NBS1 was detected in only 3 of 5 available breast tumors from NBS1 657del5-carriers. In 2 of these tumors, the loss involved the mutant NBS1-allele. Overall, our data suggest that the NBS1 657del5 allele may contribute only to a limited fraction of breast cancer cases in Russia. © 2004 Wiley-Liss, Inc.

Initiation and/or promotion of endometrial cancer is known to be associated with estrogen and androgen (androstenedione) excess as well as with hyperinsulinemia/insulin resistance. It is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to endometrial cancer susceptibility. We evaluated here the role of CYP17 biallelic (MspAI) polymorphism in 114 endometrial cancer patients compared with 182 healthy women. Our data demonstrated that A2/A2 CYP17 genotype, considered on the basis of initial breast cancer studies as 'unfavorable', was under-represented in endometrial cancer group (odds ratio 0.48, 95% confidence interval 0.25-0.89) that confirmed results of two other recent investigations. Carriers of this genotype were characterized by having lower blood insulin (by 120 min of oral glucose tolerance test 36.7+/-3.9 microU/ml vs. 90.4+/-16.7 microU/ml in postmenopausal women with A1/A1 genotype, P=0.04) and C-peptide levels (after night fasting 575.2+/-78.3 pg/ml vs. 978.9+/-115.7 pg/ml, respectively, P=0.04). No significant difference was found between the mean concentrations of testosterone, dehydroepiandrosterone sulfate and estradiol concentrations in patients-carriers of separate CYP17 genotypes. Thus, CYP17 polymorphism (namely, carrying the 'normal' A1/A1 genotype) might be one of the risk factors for endometrial cancer development. A1/A1 CYP17 variant may be associated with untraditional (non-steroidal) pathways that calls for corresponding preventive measures in high-risk groups.

Measurement of intratumoral expression of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) may have some value in predicting the response to fluoropyrimidine-containing therapy. Patients and Methods: We attempted to validate this association in a series of Russian metastatic colorectal cancer cases. While replicating already published protocols, we unexpectedly found that the use of commonly utilized gene referees, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin, may lead to artifacts due to pseudogene-driven amplification from the genomic DNA template. We have developed a real-time PCR protocol which amplifies short PCR fragments, thus allowing efficient analysis of archival formalin-fixed paraffin-embedded tumor samples, and relies on succinate dehydrogenase (SDHA) as a gene referee, therefore avoiding amplification from genomic DNA. Results: Low content of DPD transcripts was observed in 13/20 (65%) patients with disease control (tumor response or disease stabilization) as compared to only 3/9 (33%) subjects with progressive disease (p = 0.11). Despite the low number of patients, this association reached the level of statistical significance when similar analysis was done for TS expression (11/20 (55%) vs. 1/9 (11%); p = 0.03). Conclusions: Our data confirm that low DPD and TS expressors have higher chances of success of fluoropyrimidine-containing regimens.

Previous studies indicate that founder mutations may play a noticeable role in breast cancer (BC) predisposition in Russia. Here we performed a systematic analysis of eight recurrent mutations in 302 BC cases (St.-Petersburg, Russia), which were selected due to the presence of clinical indicators of hereditary disease (bilaterality and/or early onset (or =40 years) and/or family history). BC-associated alleles were revealed in 46 (15.2%) women. BRCA1 5382insC mutation was detected in 29 (9.6%) patients, CHEK2 1100delC in 9 (3.0%), BRCA1 4153delA in 3 (1.0%), CHEK2 IVS2+1GA in 2 (0.7%), and BRCA1 185delAG, BRCA2 6174delT and NBS1 657del5 in 1 (0.3%) patient each. No cases with BRCA1 300TG (C61G) mutation was identified. The obtained data suggest that a significant fraction of hereditary BC cases in Russia can be diagnosed using only a limited number of simple PCR tests.

High-frequency microsatellite instability (MSI-H) occurs frequently in colorectal cancers and some other tumor types, but is very uncommon in breast cancer. In the earlier study devoted to microsatellite analysis of allelic imbalances, the authors accidentally detected several MSI-H tumors in patients with the bilateral form of breast cancer (biBC). The present study was designed to examine this unexpected phenomenon in more detail. All DNA samples were tested by the standard panel of MSI-specific markers BAT25, BAT26, BAT40, D5S346, and D17S250. If the tumor was unstable for at least one marker, or PCR amplification was not successful for any of the listed above loci, the analysis of additional five dinucleotide markers (D1S225, D11S4167, D22S272, D22S1166, and D3S3527) was performed. Tumors showing instability in ≥30% loci were classified as MSI-H. In biBC group, MSI-H status was detected in 6/60 (10%) contralateral tumors, but in 0/50 (0%) first malignancies (P = 0.021) and only in 1/22 (5%) synchronous biBC (P = 0.434). None of 52 unilateral breast cancers showed MSI-H status. Shifts of mononucleotide markers were revealed in four second carcinomas from biBC patients but in none of the breast tumors from other categories. MSI-H is detected with a noticeable frequency in bilateral but not in unilateral breast cancers. Preferable occurrence of MSI-H in second metachronous tumors from biBC patients allows to hypothesize that the development of some contralateral breast neoplasms is casually related to the adjuvant treatment of the initial malignancy.

We applied an alternative approach to assess the controversial evidence for the role of GSTM1 and GSTT1 deficiencies (null genotypes) in cancer susceptibility. In this study setting, the prevalence of GSTM1 and GSTT1 null genotypes in the lung cancer patients (LCs, n = 167) were compared with those in the group of putatively cancer resistant individuals, i.e. elderly tumor-free donors (EDs, n = 324). Healthy middle-aged donors (HDs, n = 339) were used as another comparison group. Our results support the previous conclusions of a modest protective effect associated with presence of at least one functional copy of GSTM1 gene; the prevalence of GSTM1 deficiency in LCs (54%) did not differ from that observed in HDs (54%), but showed a significant increase when compared with EDs (45%) (OR = 1.46, 95% CI = 1.00-2.12). Furthermore, in agreement with mechanistic considerations, the GSTM1 null genotypes were more prevalent in squamous cell carcinoma patients (58%) and in lung cancer patients with seemingly low cumulative carcinogen exposure dose (non-smokers: 63%; patients aged below 50 years: 76%). Contrary to GSTM1, no significant effect in the lung cancer proneness was observed for the GSTT1 genotypes. The results of this study are thus in good agreement with the body of literature data, including several published meta-analyses. Consequently, the suggested study design involving additional "cancer resistant" group of non-affected subjects appears to provide highly demonstrative data and to be well suited for pilot investigations and for resolving controversial issues.

Excessive estrogenic influence is known to be associated with initiation/promotion of endometrial cancer (EC). Allelic polymorphisms of the genes involved in steroidogenesis/steroid metabolism may contribute to EC susceptibility. It is important to know endocrine mechanisms by which such susceptibility is acquired. Here, we compared CYP19 (aromatase) and CYP17 (17alpha-hydroxylase/17,20-lyase) gene polymorphisms correspondingly in 136 and 165 EC patients and in 116 and 188 non-affected women primarily of postmenopausal age. In these expanded studies we confirmed our previous observations that genotypes with longest alleles of CYP19 (A6 or A7) are over-represented (64.7+/-4.0 vs. 49.1+/-4.6%, P = 0.04, and 11.0+/-2.7 vs. 1.7+/-1.2%, P = 0.01)) and A2/A2 CYP17 genotype is under-represented (12.1+/-2.5 vs. 25.0+/-3.2%, P = 0.001) in patients as compared to controls. Additionally, aromatase activity was studied by tritiated water release assay in tumor tissues of 32 EC patients. In carriers of A2/A2 CYP17 genotype this activity was significantly lower than in carriers of A1/A1 genotype or in combined group of A1/A1 and A1/A2 CYP17 carriers (P = 0.04 in both cases). On the other side, intratumoral aromatase activity demonstrated tendency to higher values in carriers of longest CYP19 alleles (A6A6 and A6A7) than in carriers of all other CYP19 allele variants (P = 0.066). Thus, specific set of genetic polymorphisms (carrying of CYP17 A1 allele and combination of longest A6 or A7 CYP19 alleles) may predispose to the induction of higher rate of local estrogen biosynthesis in malignant endometrium, that in its turn may support growth of the latter. Further studies are warranted to connect revealed regularities with the type I or II of EC.