NBS1 657del5 mutation may contribute only to a limited fraction of breast cancer cases in Russia

Abstract

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...

Role of the Nijmegen Breakage Syndrome 1 Gene in Familial and Sporadic Prostate Cancer

“…Although a number of published reports have suggested that mutations in NBS1, especially 657del5, is associated with elevated risk for some cancers, including ovarian (13), breast (7,8,10), melanoma (7,9), and lymphoid malignancies (7,11,12), such findings have not been replicated in other studies (21)(22)(23)(24). For prostate cancer, Cybulski et al (5) found that the 657del5 mutation was a risk factor.…”

“…The rare variant, R215W, has also been implicated as a pathogenic mutation in Nijmegen breakage syndrome (32). Conservation studies also show that this position is highly conserved and that this change is predicted to be damaging (8,13).…”

“…This founder mutation has been found with a high frequency in the Slavic population, which includes individuals primarily from Poland, Ukraine, and the Czech Republic. A number of studies suggest that heterozygosity for a mutation in NBS1 may be associated with elevated risk for some cancers (7)(8)(9)(10)(11)(12)(13), including prostate cancer (5). Cybulski et al (5) showed an increased risk for prostate cancer among carriers of the 657del5 mutation in both familial and non-familial cases from Poland.…”

Rad50 c.687delT Does Not Contribute Significantly to Familial Breast Cancer in a French Population

“…Early reports of the contribution of mutations in different members of the MRN complex to hereditary breast cancer risk in specific populations, however, have been difficult to confirm elsewhere (8,9). A study of 435 familial breast cancer cases from the United Kingdom also failed to observe Rad50 c.687delT; in this same study, a more extensive sample of Finnish familial cases also observed no additional instances of this mutation (10).…”

Searching for susceptibility alleles: Emphasis on bilateral breast cancer

“…Nonetheless, their findings could be interpreted as an argument against the use of bilateral BC patients, especially those with synchronous form of the disease, in genetic association studies. Among the reports quoted in the Table I, only Buslov et al 21 published carrier frequencies for synchronous versus metachronous bilateral BC (1/44 (2.3%) versus 1/129 (0.78%), respectively). To extend this analysis, we have also retrieved the information from original data sets for the studies of Sokolenko et al 16 and Chekmariova et al 20 The frequency of BRCA1 5382insC mutation was 5/53 (9.4%) in synchronous and 10/91 (11.0%) in metachronous bilateral BC, i.e.…”