Heterozygous carriers of the I171V mutation of the NBS1 gene have a significantly increased risk of solid malignant tumours.

Homozygous mutation 657del5 within the NBS1 gene is responsible for the majority of Nijmegen breakage syndrome (NBS) cases. NBS patients are characterised by increased susceptibility to malignancies mainly of lymphoid origin. Recently it has been postulated that heterozygous carriers of 657del5 NBS1 mutation are at higher risk of cancer development. The aim of the study was to analyse the frequency of I171V mutation in NBS1 gene in 270 women with breast cancer, 176 patients with larynx cancer, 81 with second primary tumours of head and neck, 131 with colorectal carcinoma and 600 healthy individuals. I171V mutation was present in 17 cancer patients compared with only one in healthy individuals. This constitutes 2.58% in studied patients with malignancies and 0.17% in the control group (P=0.0002; relative risk 1.827; odds ratio 15.886; 95% confidence interval 2.107-119.8). Since DNA was isolated from non malignant cells, all mutations found in cancer patients appeared to be of germinal origin. It can be concluded that NBS1 allele I171V may be a general susceptibility gene in solid tumours.

I171V germline mutation in the NBS1 gene significantly increases risk of breast cancer.

Nijmegen Breakage Syndrome (NBS) is a rare autosomal, recessive disease caused by homozygous mutations in the NBS1 gene. The most common deletion of 5 bp (657del5) in exon 6, which affects mostly the population of Central Europe is observed. Among the typical features of this disorder is that NBS patients experience a high incidence of lymphoid malignancies as well. An increased risk of solid tumors development for 657del5 carriers was the reason to investigate the role of NBS1 gene as a susceptible one for the breast cancer. The purpose of this work is to identify mutations in all 16 exons of the NBS1 gene in the group of the patients with diagnosed breast cancer and the control group of healthy individuals. In the group of 270 women with breast cancer, seven cases of mutated NBS1 gene were revealed. In the subgroup presenting mutated NBS1 gene, the mutation I171V in 5th exon occurred in five cases. It is the first such a discovery concerning breast cancer patients because this mutation had been previously observed only in the course of lymphoid or hematological malignancies. The rate of I171V mutation in the group of breast cancer patients was significantly higher than in the controls (OR: 9.42; 95% CI: 1.09-81.05; P = 0.02). The conclusion is that heterozygous germline mutation I171V in NBS1 gene is a significant risk factor for breast cancer development. It concerns especially the women whose first degree relatives had a previously diagnosed breast cancer (OR: 6.00; 95% CI: 0.98-38.07; P = 0.04). The histopathological and clinical features of breast cancer with I171V mutation suggest accumulation of the negative prognostic factors. The treatment's results however were unexpectedly satisfactory, that is why further investigations are necessary to assess the role of I171V mutation in NBS1 gene as a prognostic and predictive factor for breast cancer.

Expression of estrogen receptor beta in the breast carcinoma of BRCA1 mutation carriers.

BACKGROUND: Breast cancers (BC) in women carrying mutations in BRCA1 gene are more frequently estrogen receptor negative than the nonhereditary BC. Nevertheless, tamoxifen has been found to have a protective effect in preventing contralateral tumors in BRCA1 mutation carriers. The identification of the second human estrogen receptor, ERbeta, raised a question of its role in hereditary breast cancer. The aim of this study was to assess the frequency of ERalpha, ERbeta, PgR (progesterone receptor) and HER-2 expression in breast cancer patients with mutated BRCA1 gene and in the control group. METHODS: The study group consisted of 48 women with BRCA1 gene mutations confirmed by multiplex PCR assay. The patients were tested for three most common mutations of BRCA1 affecting the Polish population (5382insC, C61G, 4153delA). Immunostaining for ERalpha, ERbeta and PgR (progesterone receptor) was performed using monoclonal antibodies against ERalpha, PgR (DakoCytomation), and polyclonal antibody against ERbeta (Chemicon). The EnVision detection system was applied. The study population comprised a control group of 120 BC operated successively during the years 1998-99. RESULTS: The results of our investigation showed that BRCA1 mutation carriers were more likely to have ERalpha-negative breast cancer than those in the control group. Only 14.5% of BRCA1-related cancers were ERalpha-positive compared with 57.5% in the control group (P < 0.0001). On the contrary, the expression of ERbeta protein was observed in 42% of BRCA1-related tumors and in 55% of the control group. An interesting finding was that most hereditary cancers (75% of the whole group) were triple-negative: ERalpha(-)/PgR(-)/HER-2(-) but almost half of this group (44.4%) showed the expression of ERbeta. CONCLUSION: In the case of BRCA1-associated tumors the expression of ERbeta was significantly higher than the expression of ERalpha. This may explain the effectiveness of tamoxifen in preventing contralateral breast cancer development in BRCA1 mutation carriers.