RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability

Heikkinen, Kaisa; Rapakko, Katrin; Karppinen, Sanna-Maria; Erkko, Hannele; Knuutila, Sakari; Lundán, Tuija; Mannermaa, Arto; Børresen-Dale, Anne Lise; Borg, Åke; Barkardóttir, Rósa B.; Petrini, John H.J.; Winqvist, Robert

doi:10.1093/carcin/bgi360

Cited by 182 publications

(145 citation statements)

References 26 publications

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“…Interestingly, an association between a specific lowpenetrance mutation of RAD50 and susceptibility to hereditary breast cancer has been reported recently, and mutation carriers show increased spontaneous chromosomal aberrations in their peripheral blood T lymphocytes (38), consistent with the role of MRN in maintaining genomic stability. In a recent study which looked for mutation in the consensus coding sequences of 13,023 genes in breast cancer tumor tissue, Mre11 was identified as one of the hotspots of mutation (39).…”

Section: Discussionmentioning

confidence: 56%

Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex

Hsu

Wang

Chen

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The evolutionarily conserved Mre11-Rad50-Nbs1 (MRN) complex, consisting of proteins encoded by the genes Mre11, Rad50, and Nbs1, was recently shown to play a crucial role in DNA double-strand break (DSB) repair by recruiting the nuclear protein kinase ataxia telangiectasia mutated to DSB sites, leading to activation of this DNA repair network. Given the fact that carriers of defective mutation and polymorphic variants of ataxia telangiectasia mutated are at higher risk of developing breast cancer, we hypothesized a role of the MRN genes in determining breast cancer susceptibility. This hypothesis was examined both in a case control study of 559 breast cancer patients and 1,125 healthy women of single-nucleotide polymorphisms in Mre11, Rad50, and Nbs1 and by the in vivo detection of binding between Mre11 and BRCA1, encoded by the breast cancer susceptibility gene BRCA1. We were also interested in defining whether any association between MRN genes and breast cancer was modified by reproductive risk factors reflecting the level of estrogen exposure or susceptibility to estrogen exposure, as estrogen is known to initiate breast cancer development due to its metabolites causing DSB formation. Support for the hypothesis came from the observations that (a) one single-nucleotide polymorphism in Nbs1 was significantly associated with breast cancer risk, and a trend toward an increased risk of developing breast cancer was found in women harboring a greater number of putative high-risk genotypes of MRN genes (an adjusted odds ratio of 1.25 for each additional putative high-risk genotype; 95% confidence interval, 1.10-1.44); (b) this association between risk and the number of putative high-risk genotypes was stronger and more significant in women thought to be more susceptible to estrogen, i.e., those with no history of full-term pregnancy, those older (z26 years of age) at first full-term pregnancy, or those having had fewer (<2) full-term pregnancies; the risk effect conferred by harboring a higher number of high-risk genotypes of MRN genes was more significant in women without a history of breast feeding; and (c) Mre11 and BRCA1 were shown to form a complex in vivo, and this interaction was increased by irradiation. This study supports the role of the MRN pathway in breast cancer development, further strengthening the suggestion that mechanisms regulating DSB repair may play a mutator role driving breast cancer pathogenesis. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2024 -32)

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Section: Discussionmentioning

confidence: 56%

Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex

Hsu

Wang

Chen

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…For example, variants of DNA repair genes have been shown to confer breast cancer susceptibility via genomic instability (e.g., RAD50 and NBS1; ref. 38).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Linkage Analysis of TMPRSS2-ERG Fusion in Familial Prostate Cancer

et al. 2009

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Fusion of the 5 ¶-untranslated region of androgen-regulated TMPRSS2 promoter with ETS transcription factor family members is found frequently in prostate cancers, and recent work suggests that the most common TMPRSS2-ERG fusion is associated with an aggressive clinical phenotype compared with fusion-negative prostate cancer. Thus far, analysis of the fusion has been limited to sporadic cases of prostate cancer. In the current study, we explore for an enrichment of TMPRSS2-ERG fusion in familial prostate cancer. TMPRSS2-ERG fusion was identified using a break-apart fluorescence in situ hybridization assay on tissue microarrays. Presence of TMPRSS2-ERG fusion was associated with higher Gleason scores (P = 0.027). Of 75 patients with established history of prostate cancer, we detected the TMPRSS2-ERG fusion in 44 (59%) patients. Almost three quarters (73%) of fusionpositive patients accumulated within 16 specific families whereas only 27% were single fusion-positive cases within one family. Based on reported prevalence rates, we calculated a sibling recurrence risk ratio of up to 18.9. A subset (63%) of families with uniformly TMPRSS2-ERG-positive prostate cancer underwent a genome-wide linkage scan at 500 markers. This revealed several loci located on chromosomes #9, #18, and X that were suggestive of linkage to the TMPRSS2-ERG fusion-positive prostate cancer phenotype with linkageof-disease scores up to 2.16 and nonparametric linkage scores up to 2.77. This suggests the presence of an inherited susceptibility to developing the TMPRSS2-ERG fusion. Given the association of TMPRSS2-ERG fusion and aggressive prostate cancer, close surveillance of relatives of patients with established fusion-positive prostate cancer or a family history of prostate cancer in general would be warranted.

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“…40 Similar to former reports on breast cancer families carrying mutations in ATM, CHEK2 or BRIP1, 37,38,51, 54 Rahman et al 40 reported that only two of four first-degree breast cancer-affected relatives of breast cancer probands with PALB2 mutations also carried the PALB2 mutations, indicating an incomplete segregation of PALB2 mutations with breast cancer and thereby mirroring the difficulties of screening these genes in breast cancer families when unaffected women ask for predictive molecular testing to specify their individual breast cancer risk. In addition, ATM, BRIP1, CHEK2 and 41 identified the Finnish founder mutation 687delT, which is associated with an increased breast cancer risk (odds ratio 4.3) in the Finnish cohort (n ¼ 317). But, subsequent analyses in additional cohorts from Sweden, Norway and Iceland (n ¼ 512) failed to identify the mutation, thus again indicating the high frequency of certain mutations in distinct populations that has to be considered if molecular screening is discussed.…”

Section: Breast Cancer Susceptibilitymentioning

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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RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability

Cited by 182 publications

References 26 publications

Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex

Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex

Genome-Wide Linkage Analysis of TMPRSS2-ERG Fusion in Familial Prostate Cancer

Breast cancer susceptibility: current knowledge and implications for genetic counselling

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