Nijmegen Breakage Syndrome mutations and risk of breast cancer

Bogdanova, Natalia; Feshchenko, Sergei; Schürmann, Peter; Waltes, Regina; Wieland, Britta; Hillemanns, Peter; Rogov, Yuriy; Dammann, Olaf; Bremer, Michael; Karstens, Johann H.; Sohn, Christof; Varon, Raymonda; Dörk, Thilo

doi:10.1002/ijc.23168

Cited by 123 publications

(101 citation statements)

References 33 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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Nijmegen breakage syndrome is characterized by genomic instability and a predisposition for lymphoma and solid tumors. Nijmegen breakage syndrome 1 (NBS1), the protein which is mutated in these patients, functions in association with BRCA1 and ATR as part of the cellular response to DNA double-strand breaks. We show here that NBS1 forms foci at the centrosomes via an interaction with ;-tubulin. Down-regulation of NBS1 by small interfering RNA induces supernumerary centrosomes, and this was confirmed with experiments using Nbs1 knockout mouse cells; the introduction of wild-type NBS1 (wt-NBS1) cDNA into these knockout mouse cells reduced the number of supernumerary centrosomes to normal levels. This phenotype in NBS1-deficient cells is caused by both centrosome duplication and impaired separation of centrioles, which have been observed in BRCA1-inhibited cells. In fact, supernumerary centrosomes were observed in Brca1 knockout mouse cells, and the frequency was not affected by NBS1 down-regulation, suggesting that NBS1 maintains centrosomes via a common pathway with BRCA1. This is consistent with findings that NBS1 physically interacts with BRCA1 at the centrosomes and is required for BRCA1-mediated ubiquitination of ;-tubulin. Moreover, the ubiquitination of ;-tubulin is compromised by either ATR depletion or an NBS1 mutation in the ATR interacting (FHA) domain, which is essential for ATR activation. These results suggest that, although centrosomes lack DNA, the NBS1/ATR/ BRCA1 repair machinery affects centrosome behavior, and this might be a crucial role in the prevention of malignances.

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Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…26 Recently, a 5 bp deletion in NBN (657del5) was shown to be associated with an almost threefold increase in breast cancer risk for heterozygous female carriers in Central and Eastern Europe. 18 Finally, some studies reported an elevated breast cancer risk in hereditary non-polyposis colorectal cancer (HNPCC/ Lynch syndrome, MIM no. 120435) caused by heterozygous mutations in DNA mismatch repair genes, mainly MLH1, MSH2, MSH6 and PMS2, 27,28 whereas other investigations showed no or only a slightly increased breast cancer risk.…”

Section: Breast Cancer-associated Cancer Predisposition Syndromesmentioning

confidence: 99%

Breast cancer susceptibility: current knowledge and implications for genetic counselling

et al. 2008

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Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.

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“…Breast Cancer Susceptibility Gene List [8,9,11,13,17,19,20], [35][36][37][38][39][40][41][42][43][44][45][46][47] …”

Section: Additional Filementioning

confidence: 99%

Clinical and genetic characterization of hereditary breast cancer in a Chinese population

Jian

Shao

Qin

et al. 2017

Hered Cancer Clin Pract

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Background: Breast cancer develops as a result of multiple gene mutations in combination with environmental risk factors. Causative variants in genes such as BRCA1 and/or BRCA2 have been shown to account for hereditary nature of certain breast cancers. However,other genes, such as ATM, PALB2, BRIP1, CHEK, BARD1, while lower in frequency, may also increase breast cancer risk. There are few studies examining the role of these causative variants. Our study aimed to examine the clinical and genetic characterization of hereditary breast cancer in a Chinese population. Methods: We tested a panel of 27 genes implicated in breast cancer risk in 240 participants using Next-Generation Sequencing. The prevalence of genetic causative variants was determined and the association between causative variants and clinico-pathological characteristics was analyzed. Results: Causative variant rate was 19.2% in the breast cancer (case) group and 12.5% in the high-risk group. In the case group 2.5% of patients carried BRCA1 causative variant, 7.5% BRCA2 variants, 1.7% patients had MUTYH, CHEK or PALB2 variants, and 0.8% patients carried ATM, BARD1, NBN, RAD51C or TP53 variants. In the high-risk group 5. 8% women carried MUTYH causative variants, 2.5% had causative variants in ATM, 1.7% patients had variants in BRCA2 and 0.8% in BARD1, BRIP1 or CDH1. There was no significant difference in the presence of causative variants among clinical stages of breast cancer, tumor size and lymph nodes status. However, eight of the 12 BRCA1/2 causative variants were found in the TNBC group. Conclusions: We found increased genetic causative variants in the familial breast cancer group and in high-risk women with a family history of breast cancer. However, the variant MUTYH c.892-2A > G may not be directly associated with hereditary breast carcinoma.

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Nijmegen Breakage Syndrome mutations and risk of breast cancer

Cited by 123 publications

References 33 publications

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

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

Breast cancer susceptibility: current knowledge and implications for genetic counselling

Clinical and genetic characterization of hereditary breast cancer in a Chinese population

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