Bilateral breast cancer (biBC) is a common form of breast cancer; however, it has not been subjected to systematic comparative genetic studies. We allelotyped 28 biBCs on 14 chromosomal arms, addressing 2 lines of questions: (

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.

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...

The coexistence of type 2 diabetes with breast cancer may result in poorer cancer-related survival due to a number of mediating factors including an alteration of tumor tissue hormonal sensitivity. Previous studies have shown that receptor status of breast tumors in diabetics may be changed; however, the mode of therapy for diabetes was usually ignored. This work presents the results of an analysis of the receptor status of breast carcinomas in 90 postmenopausal women suffering with diabetes mellitus type 2 who had been cured, for not less that 1 year prior to surgery, with different modes of antidiabetic therapy, including a dietary treatment only, sulfonylurea preparations, insulin therapy, and metformin as a monotherapy or in combination with sulfonylurea derivatives. No differences in estrogen receptors occurrence in tumor tissue were found in different treatment groups. The frequency of progesterone receptor-positive mammary carcinomas in women who were treated with metformin, irrespective of whether it was combined with sulfonylurea preparations, was significantly higher than in the sulfonylurea only group (P=0.043) and in the combined group of patients treated with either sulfonylurea or insulin (P=0.041). The exclusion of the patients who received neoadjuvant chemotherapy (24 persons) did not significantly affect the above results. The data may be used as an explanation of the distinctions in cancer characteristics and course between diabetic patients treated with either metformin or sulfonylurea derivatives and insulin.

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Amplification of HER2, C-MYC and CCND1 oncogenes is a hallmark of breast cancer (BC); however, its involvement in the bilateral form of this disease has not been investigated yet. In this study, 50 bilateral BC (biBC) pairs (100 tumors) and 72 control unilateral BC were examined using real-time PCR analysis of microdissected archival tissues. In biBC, the frequency of >3-fold oncogene amplification was 6/100 (6%) for HER2, 6/100 (6%) for C-MYC and 7/100 (7%) for CCND1. Altogether, 18/100 (18%) biBC tumors had increased gene dosage of at least one oncogene. Tumors forming synchronous biBC pairs had amplification in 11/46 cases (24%). In 3 of 8 patients with amplification-positive carcinomas, the amplification was detected in both neoplasms: 2 biBC had concordant activation of the same oncogene (HER2 and CCND1, respectively), and in the remaining case distinct oncogenes were affected (HER2 and C-MYC). In contrast, amplifications in metachronous biBC were strongly discordant: none of 27 first carcinomas carried this abnormality, while the frequency of amplification in second tumors (7/27; 26%) was similar to the one observed in unilateral BC (20/72; 28%). The trend toward concordance of oncogene amplification status in synchronous but not in metachronous biBC pairs can be explained by the nearly identical natural history of the disease in simultaneously arising tumors. The skewed pattern of amplifications in metachronous biBC might be attributed to their association with adverse BC prognosis; it appears that only patients with amplification-negative first BC have sufficient chances to survive until the development of the contralateral carcinoma. ' 2006 Wiley-Liss, Inc.

Background:As endometrial cancer (EC) prevalence increases with obesity, we aimed to determine whether EC characteristics depend upon obesity type: ‘standard’ (SO) or ‘metabolically healthy obesity’ (MHO).Patients & methods:258 EC patients were included. Data on anthropometry, blood hormones, lipids and glucose, and tumor features were collected.Results:EC clinicopathologic characteristics and clinical stage correlate differently with BMI and obesity type. BMI is related inversely with tumor grade while SO patients are characterized by a more advanced clinical stage than those with MHO. Besides typical insulin resistance signs, EC patients with SO often display a higher serum leptin/adiponectin ratio compared with MHO patients. Historical data suggest a gradual increase in EC patient height and weight, and a decrease in MHO prevalence.Conclusion:It is currently unknown whether the latter observation reflects the evolution of EC, or obesity alongside the current epidemic. Regardless, the reduced MHO prevalence demonstrates the need for more intensive preventive measures aimed at obesity and obesity-associated conditions, including different EC subtypes.

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