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

Abstract

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.

Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway

“…Mutant NBS1 carriers have a 3-fold to 9-fold increased risk of breast cancer, although this varies with ethnic background (18,19). Moreover, epidemiologic studies have indicated that a reduced expression of NBS1 is observed in up to 80% of breast cancer cases without any reported mutations (45,46).…”

“…NBS1 mutant carriers also have a high risk for solid tumors, including breast cancer (18)(19)(20). Cells derived from such patients show defects in cellular responses to the presence of DNA doublestrand breaks (DSB), such as homologous recombination repair (21,22) and an abnormal regulation of checkpoints (23)(24)(25).…”

RAD50 gene mutations are not likely a risk factor for breast cancer in Poland

“…In our previous study, we showed that the germline p.I171V mutation in NBN, one of the M/R/N genes, may be considered as a risk factor in the development of solid malignant tumor including breast cancer, larynx and colorectal cancer [3][4][5] or acute lymphoblastic leukemia [6]. Heterozygous carriers of the NBN c.657del5 mutation have an increased risk of malignant tumor development, especially of breast cancer [7,8], prostate [9], and colon and rectal cancer [7].…”

“…The DNA isolation procedure was described in our previous study [3]. The research protocol was approved by the ethics committee, Poznan University of Medical Sciences and all patients signed the informed consent form.…”

A Rare Polymorphic Variant of NBS1 Reduces DNA Repair Activity and Elevates Chromosomal Instability

“…To date, the NBS1-I171V polymorphic variant was detected frequently only in Polish patients with breast cancer, head and neck cancer, and colorectal cancer (25)(26)(27)(28). However, other groups did not find a similar association in European patients with breast cancer, leukemia, or lymphoma (29)(30)(31).…”