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The BLM gene belongs to the RecQ helicase family and has been implicated in the maintenance of genomic stability. Its homozygous germline inactivation causes Bloom syndrome, a severe genetic disorder characterized by growth retardation, impaired fertility and highly elevated cancer risk. We hypothesized that BLM is a candidate gene for breast cancer (BC) predisposition. Sequencing of its entire coding region in 95 genetically enriched Russian BC patients identified two heterozygous carriers of the c.1642 C>T (Q548X) mutation. The extended study revealed this allele in 17/1,498 (1.1%) BC cases vs. 2/1,093 (0.2%) healthy women (p 5 0.004). There was a suggestion that BLM mutations were more common in patients reporting first-degree family history of BC (6/251 (2.4%) vs. 11/1,247 (0.9%), p 5 0.05), early-onset cases (12/762 (1.6%) vs. 5/736 (0.7%), p 5 0.14) and women with bilateral appearance of the disease (2/122 (1.6%) vs. 15/1376 (1.1%), p 5 0.64). None of the BLM-associated BC exhibited somatic loss of heterozygosity at the BLM gene locus. This study demonstrates that BLM Q548X allele is recurrent in Slavic subjects and may be associated with BC risk.Hereditary risk factors are strongly implicated in breast cancer (BC) predisposition. Mutations in BRCA1 and BRCA2 genes account for approximately 15-20% of familial BC clustering among first degree relatives.

There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning.

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...