RAD50 and NBS1 are not likely to be susceptibility genes in Chinese non-BRCA1/2 hereditary breast cancer

Abstract

Deleterious mutations in several genes that are involved in repair of damage to DNA have been associated with an increased risk of breast cancer. Recent studies have shown sequence variants in two such genes, RAD50 and NBS1, which can be predisposed to breast cancer. The aim of this study is to elucidate the contribution of RAD50 and NBS1 germline mutations to the etiology of non-BRCA1/2 hereditary breast cancer in China. We conducted a mutational analysis of RAD50 and NBS1 in genomic DNA from 384 Chinese women with early-onset breast cancer and/or affected relatives. All the coding exons and adjacent intronic splice junction rejoins of RAD50 and NBS1 were screened using PCR-DHPLC and DNA sequencing analysis. Among all cases, no obviously deleterious mutations were observed in RAD50; one synonymous change c.102G>A at codon 34 and one single nucleotide polymorphism IVS9 + 19C>T were identified in NBS1. Furthermore, there was no remarkable difference in the allele frequency of NBS1 c.553G>C (E185Q) between cases (172/384) and controls (182/420). Our results exclude the possible role of RAD50 and NBS1 in familial breast cancer predisposition in Chinese women, and there is no evidence for the recommendation of RAD50 and NBS1 for genetic testing in China.

Heterozygous germline mutations in NBS1 among Korean patients with high-risk breast cancer negative for BRCA1/2 mutation

“…Therefore, we could not confirm a pathogenic effect of heterozygous p.I171V in breast cancer even though the variant was predicted to be deleterious by both the PolyPhen-2 and SIFT algorithms. Similar to our result, several other casecontrol studies failed to find a significant relationship between heterozygous p.I171V and risk of breast cancer [15,17,18,20]. In addition to p.I171V, another common NBS1 variant, c.657del5, has been tested for its significance in breast cancer.…”

“…Cao et al [20] tested variants p.I171V, p.Q185E, and c.657del5 in the NBS1 gene among Chinese non-BRCA1/2 high-risk breast cancer and found that no patient carried the p.I171V or c.657del5 variant. This result was reconfirmed in subsequent research by the same group [18].…”

“…Although these variants have been found in breast cancer patients from several European countries, a significant association with the risk of breast cancer has only been demonstrated in Polish patients (Table 3). Sequence variants in the NBS1 gene have been tested in a few studies of Asian patients with breast cancer: however, mutations that are are commonly reported in European patients were not detected [18,20,32]. In the current study, we found 4 Korean patients with the p.I171V variant in a heterozygous status among 235 patients with non-BRCA1/2 high-risk breast cancer.…”

“…Although most of these studies were conducted on Western populations, a few have focused on Asian patients. However, no deleterious germline mutation in the NBS1 gene was found among Asian patients with breast cancer [18][19][20].…”

Protein-truncating variants in moderate-risk breast cancer susceptibility genes: A meta-analysis of high-risk case-control screening studies

“…Studies performed on French Canadian and Chinese populations did not detect any PTVs in either high-risk cases or controls (35,36). Overall, by using the fixed and random effects models, we found an aggregated odds ratio for these four studies of 3.10 (95% CI 1.148-8.42) for the NBS1 PTVs.…”