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...

Dear Sirp53 codon 72 Arg/Pro polymorphism appears to be one of the most promising low-penetrance candidates for breast cancer predisposition. Indeed, p53 Pro allele is among a very few genetic variants, which retain the unfavorable significance upon the systematic meta-analysis of breast cancer polymorphic genes. 1 In addition, there is sound biological evidence arguing for the functional difference between Arg and Pro alleles. These variants have the distinct ability to mediate HPV E6 protein degradation, activate transcription of p53-responsive genes, induce apoptosis and suppress malignant transformation in at least some experimental systems. 2-4 Furthermore, p53 codon 72 polymorphism may be a subject of natural selection by the level of sun exposure, as its frequency gradually changes with latitude. 5 In recognition of the crucial impact of the p53 gene in tumor development, the epidemiology of the Arg/Pro allele variations was tested intensively for all major cancer types, including lung, cervical, colorectal, bladder and other neoplasms. Unfortunately, none of the reported gene-disease associations demonstrated consistency in the literature. 2,4,6 -9 Despite promising assumptions, the role of the Arg/Pro allelism in breast cancer susceptibility was examined in only a few reports and some of these had a very small number of observations. 10 -15 We have re-assessed the hypothesis on involvement of p53 polymorphism in the determination of breast cancer risk. In addition to a traditional comparison of breast cancer patients (n ϭ 448; mean age ϭ 55.4 years; age range: 29 -83 years) and healthy female donors (n ϭ 249; mean age ϭ 38.5 years; age range: 18 -54 years), we attempted to increase the demonstrability of the study by invoking the subjects with extreme degrees of either breast cancer predisposition or cancer tolerance. In particular, we also genotyped 81 bilateral breast cancer patients (mean age at onset of the first tumor: 49.5 years; age range: 30 -85 years; mean age at onset of the contralateral tumor: 56.5 years; age range: 37-87 years) as well as 144 elderly tumor-free women (mean age ϭ 79.5 years; age range: 75-90 years). Histologically confirmed cases of unilateral and bilateral breast cancer were collected in N.N. Petrov Institute of Oncology (St.-Petersburg, Russia). Female donors were randomly recruited from the blood transfusion unit located in the same hospital; a medical permit to donate blood was considered to be sufficient proof of their healthy status. Elderly tumor-free women were enrolled from various hospitals of St.-Petersburg; results of the current clinical examination, previous records of health professionals and information obtained by questionnaires were taken into consideration to ensure the lack of cancer history for elderly subjects. All affected and non-affected subjects were Caucasians of Slavic origin residing in St.-Petersburg, Russia. Peripheral leukocytes were the source of normal DNA for unilateral breast cancer patients as well as for middle-aged and elderly contro...

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