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+1G>A in 2 (0.7%), and BRCA1 185delAG, BRCA2 6174delT and NBS1 657del5 in 1 (0.3%) patient each. No cases with BRCA1 300T>G (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.

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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. Key words: NBS1 gene; germline mutation; founder mutation; breast cancer; predisposition Intensive studies on genetic aspects of breast cancer (BC) susceptibility led to the identification of a number of BC-predisposing genes. BRCA1 and BRCA2 together account for approximately 20% of familial BC clustering. 1 In a broad sense, ATM and p53 germline mutations, predisposing to ataxia-telangiectasia and Li-Fraumeni hereditary syndromes, respectively, can be considered as BC-associated genetic defects as well, owing to the increased incidence of breast neoplasia in their heterozygous carriers. 2 Recently, the 5th breast cancer gene, CHEK2, has been identified, although its penetrance appears to be relatively moderate. 3 Strikingly, all so far known BCpredisposing genes participate in the recognition and/or cellular response to the DNA damage. Therefore, it is likely that further investigation of safeguards of genomic integrity will allow the discovery of new determinants of breast cancer heritability.In light of these assumptions, evidence for the involvement of the NBS1 gene in breast cancer susceptibility draws a high level of attention. The NBS1 protein, called nibrin, contributes to a variety of processes protecting the chromosomal stability, including sensing DNA damage, double-strand break repair, telomere maintenance, cell cycle checkpoint regulation, etc. Furthermore, proper functioning of NBS1 is important for those cellular events, which require "physiological" double-strand breaks, e.g., meiosis and V(D)J recombination. Homozygous truncating germline mutations in the NBS1 gene cause so-called Nijmegen chromosomal breakage syndrome (NBS), a rare recessive life-threatening condition named after the Dutch city where this disease was discovered in 1981. Patients with the NBS syndrome are characterized by "birdlike" facial appearance, microcephaly, immun...

If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2*1100delC should be f5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be f9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2*1100-delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P trend = 0.0003) and Finland (P trend = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2*1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2*1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2*1100delC and other moderate penetrance alleles in women with a family history of breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):230 -4)

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.