RAD50 gene mutations are not likely a risk factor for breast cancer in Poland

Mosor, Maria; Ziółkowska-Suchanek, Iwona; Rożnowski, Krzysztof; Baranowska, Marta; Januszkiewicz‐Lewandowska, Danuta; Nowak, Jerzy

doi:10.1007/s10549-010-0992-y

Cited by 11 publications

(14 citation statements)

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“…These missense variants have been reported previously in the UK familial breast cancer patients (one p.V127I, two p.V315L carriers among 435 cases) but not in controls [15]. In our former study, the p.V127I variant was observed in one out of 280 breast cancer patients and in one individual among 328 controls [16]. The in silico analysis did not reveal possible damaging functional effect of these two variants on the RAD50 protein.…”

Section: Discussionsupporting

confidence: 62%

“…To date, the association of the molecular variants in the RAD50 and MRE11 gene with the cancer risk has not been so extensively studied. Although, the germline c.687delT mutation in RAD50 has been linked to sporadic breast cancer in the Finnish population [14,15], our results excluded the mutation as a risk variant in Polish breast cancer patients [16]. Other molecular variants in the RAD50 gene: p.I94L in exon 3 and p.R224H in exon 5, intronic variant IVS3-1G>A and a nonsense mutation p.Q350X in exon 7 have been observed at a low frequency not allowing to determine whether the variants increased the risk of breast cancer.…”

Section: Introductionmentioning

confidence: 79%

“…All samples were analyzed by PCR multi-temperature single-strand conformation polymorphism (PCR-MSSCP) technique (Biovectis, Warsaw, Poland). The exons 2, 5, 6, 7, 10, 13 of the NBN gene and the exons 3, 4, 5 and 7 of the RAD50 gene were analyzed as described in our previous studies [6,16]. Screening of the regions of the MRE11 was performed using the primers flanking the exons 5, 9, 10, 14, 15, 19 and exon/intron boundaries (primer sequences as Additional file 1).…”

Section: Methodsmentioning

confidence: 99%

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Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia

et al. 2013

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BackgroundThe MRE11, RAD50, and NBN genes encode proteins of the MRE11-RAD50-NBN (MRN) complex involved in cellular response to DNA damage and the maintenance of genome stability. In our previous study we showed that the germline p.I171V mutation in NBN may be considered as a risk factor in the development of childhood acute lymphoblastic leukemia (ALL) and some specific haplotypes of that gene may be associated with childhood leukemia. These findings raise important questions about the role of mutations in others genes of the MRN complex in childhood leukemia. The aim of this study was to answer the question whether MRE11 and RAD50 alterations may be associated with childhood ALL or AML.MethodsWe estimated the frequency of constitutional mutations and polymorphisms in selected regions of MRE11, RAD50, and NBN in the group of 220 children diagnosed with childhood leukemias and controls (n=504/2200). The analysis was performed by specific amplification of region of interest by PCR and followed by multi-temperature single-strand conformation polymorphism (PCR-MSSCP) technique. We performed two molecular tests to examine any potential function of the detected the c.551+19G>A SNP in RAD50 gene. To our knowledge, this is the first analysis of the MRE11, RAD50 and NBN genes in childhood leukemia.ResultsThe frequency of either the AA genotype or A allele of RAD50_rs17166050 were significantly different in controls compared to leukemia group (ALL+AML) (p<0.0019 and p<0.0019, respectively). The cDNA analysis of AA or GA genotypes carriers has not revealed evidence of splicing abnormality of RAD50 pre-mRNA. We measured the allelic-specific expression of G and A alleles at c.551+19G>A and the statistically significant overexpression of the G allele has been observed. Additionally we confirmed the higher incidence of the p.I171V mutation in the leukemia group (7/220) than among controls (12/2400) (p<0.0001).ConclusionThe formerly reported sequence variants in the RAD50 and MRE11 gene may not constitute a risk factor of childhood ALL in Polish population. The RAD50_rs17166050 variant allele is linked to decreased ALL risk (p<0.0009, OR=0.6358 (95%CI: 0.4854-0.8327)). Despite the fact that there is no splicing abnormality in carriers of the variant allele but an excess of the G over the A allele was consistently observed. This data demonstrate that some specific alternations of the RAD50 gene may be associated with childhood ALL.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 79%

Section: Methodsmentioning

confidence: 99%

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Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia

et al. 2013

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“…Among the identified RAD50 variants, 687delT was considered as a founder mutation in Finnish population [7,11]. Nevertheless, this variant appears to be with a low frequency in Russia [12], and even lower in the UK, French, and Polish populations [11,13,14]. As for the 657del5 of NBS1, though a series of studies have provided consistent evidences supporting this Slavic founder mutation was responsible for the incidence of a significant portion of inherited breast cancer [8,[15][16][17], subsequent studies failed to confirm this association in other ethnic groups [12,18].…”

Section: Discussionmentioning

confidence: 99%

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

Cao

et al. 2011

Breast Cancer Res Treat

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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.

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“…Genes whose products are known to interact with BRCA1/2 and to be involved in DNA repair or cell cycle regulation are particularly attractive candidates for breast cancer susceptibility genes [22,60]. As a consequence, genes such as ATM, BRIP1, CHEK2, NBS1, PALB2, RAD50 and BARD1 have been analysed for the presence of germline mutations which may explain increased breast and/or ovarian cancer risk [8,12,16,23,35,38,43,46,48,50,[53][54][55].…”

Section: Introductionmentioning

confidence: 99%

Cancer predisposing BARD1 mutations in breast–ovarian cancer families

Ratajska

Antoszewska

Piskorz

et al. 2011

Breast Cancer Res Treat

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The breast cancer susceptibility gene BARD1 (BRCA1-associated RING domain protein, MIM# 601593) acts with BRCA1 in DNA double-strand break (DSB) repair and also in apoptosis initiation. We screened 109 BRCA1/2 negative high-risk breast and/or ovarian cancer patients from North-Eastern Poland for BARD1 germline mutations using a combination of denaturing high-performance liquid chromatography and direct sequencing. We identified 16 different BARD1 sequence variants, five of which are novel. Three of them were suspected to be pathogenic, including a protein truncating nonsense mutation (c.1690C>T, p.Gln564X), a splice mutation (c.1315-2A>G) resulting in exon 5 skipping, and a silent change (c.1977A>G) which alters several exonic splicing enhancer motifs in exon 10 and results in a transcript lacking exons 2-9. Our findings suggest that BARD1 mutations may be regarded as cancer risk alleles and warrant further investigation to determine their actual contribution to non-BRCA1/2 breast and ovarian cancer families.

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RAD50 gene mutations are not likely a risk factor for breast cancer in Poland

Cited by 11 publications

References 14 publications

Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia

Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia

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

Cancer predisposing BARD1 mutations in breast–ovarian cancer families

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