Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland

Abstract

Recent studies have demonstrated that heterozygous carriers of the NBS1 657del5 mutation have an increased risk for familial and bilateral breast cancer, but similar studies in consecutive breast cancer patients were inconclusive. Here, in a study of 562 nonselected breast cancer patients from Central Poland, we found 11 (1.96%) 657del5 mutation carriers vs. 3.47 expected (OR 3.21, 95%CI: 1.36-7.61, p 5 0.0107) and only 9 (1.6%) carriers of the 5382insC mutation of the BRCA1 gene, most frequently found among breast cancer patients in Poland. No carriers of R215W, another pathogenic mutation of the NBS1 gene, were found in the present study. All carriers of the 657del5 mutation had sporadic breast tumors while 5 of 9 5382insC carriers had a family history of breast/ovarian cancer or bilateral breast carcinoma. In the pooled group of patients from the present and our previous study, carried out also in patients from Central Poland, we obtained the following risk estimates (OR) for 657del5 carriers, as related to the age at breast cancer diagnosis: <40 years: 8.36; (95%CI: 2.57-27.27) p 5 0.0003; <50 years: 4.27 (95%CI: 1.67-10.89) p 5 0.003; 50 years: 2.40 (95%CI: 0.91-6.35) p 5 0.1250; all ages: 3.13 (95% CI: 1.40-7.00) p 5 0.0066. These findings demonstrate conclusively that NBS1 657del5 mutation carriers have a significantly, though moderately increased, age-related risk of breast cancer, and imply that in populations with a high 657del5 carrier frequency this mutation may contribute substantially to the overall incidence of breast cancer, particularly in younger age groups. ' 2006 Wiley-Liss, Inc.

Increased risk of larynx cancer in heterozygous carriers of the I171V mutation of the NBS1 gene

“…The frequency of 657del5 mutation carriers is relatively high in Slavic populations, reaching 1/177 in southern and 1/162 in central regions of Poland. (10,23) In contrast to our study, three 657del5 mutation carriers with cancer, described by Steffen et al, (23,27) had developed a second primary tumor. Recent findings for large groups of Polish patients strongly suggest the elevated risk of sporadic lymphoid malignancies (ALL 3/270 and NHL 2/212), (29) NHL (6/186), especially of the gastrointestinal tract, (28) and breast cancer (11/562) (27) in heterozygous 657del5 mutation carriers.…”

“…(10,23) In contrast to our study, three 657del5 mutation carriers with cancer, described by Steffen et al, (23,27) had developed a second primary tumor. Recent findings for large groups of Polish patients strongly suggest the elevated risk of sporadic lymphoid malignancies (ALL 3/270 and NHL 2/212), (29) NHL (6/186), especially of the gastrointestinal tract, (28) and breast cancer (11/562) (27) in heterozygous 657del5 mutation carriers. However, the potential link between the 657del5 mutation and cancer risk could not be proven in a Slavic (Czech) population in patients with Hodgkin's/NHL (36) and in non-Slavic populations with low population frequencies of 657del5, for example, in German patients with NHL (37,38) or breast cancer, (39) in British children with primary leukemia and primary lymphoma, (35) and in Japanese patients with B-cell malignant lymphoma.…”

“…ovarian cancer, (25) breast cancer (26,27) and NHL. (28,29) The aim of our research was to assess whether mutations in the NBS1 gene may contribute to the development of larynx cancer (LC) and MPT of the head and neck.…”

“…(17) Heterozygous mutations in the NBS1 gene have been described in various groups of cancer patients, for example, patients with acute lymphoblastic leukemia (ALL), (18,19) non-Hodgkin's lymphoma (NHL), (20) and in cancer cell lines. (21) Recent studies strongly suggest that heterozygous 657del5 mutation carriers have an elevated risk of malignant tumor development, especially of melanoma, (22,23) colon and rectum cancer, (23) prostate cancer, (24) ovarian cancer, (25) breast cancer (26,27) and NHL. (28,29) The aim of our research was to assess whether mutations in the NBS1 gene may contribute to the development of larynx cancer (LC) and MPT of the head and neck.…”

Understanding the role of the MYB oncogene in human breast cancer: targets and functions

“…In the BIR pathway, when the second DSB end is absent, the D-loop intermediate can turn into a replication fork that lead to DNA strand synthesis (Malkova et al, 1996). Many proteins that are involved in HR-mediated DNA repair are now recognized to also contribute to hereditary breast cancer risk including ATM , CHEK2 (Consortium, 2004), BARD1 (De Brakeleer et al, 2010), BRIP1 , MRE11, RAD50, NBS1 (Steffen et al, 2006, Damiola et al, 2014, RAD51C (Meindl et al, 2010) and PALB2 (Rahman et al, 2007).…”