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

Uhrhammer, Nancy; Delort, Laëtitia; Bignon, Yves Jean

doi:10.1158/1055-9965.epi-08-0971

Cited by 12 publications

(9 citation statements)

References 9 publications

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“…The mutation generates a truncated protein without the C-terminal site and has been recognized as a risk factor of familial and sporadic breast cancer in Finnish population [14]. The occurrence of the RAD50 687delT mutation in familial/non familial breast cancer in Polish, UK, French and Chinese populations has not been confirmed [15,16,32,33]. Similar frequency of this mutation in cancer patients and controls and the lack of segregation with cancer suggest that it does not increase the risk of cancer development.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…This pathogenic mutation generates a truncated protein without the important C-terminal site and it is a founder mutation in Finland, which increases 4-fold risk of breast cancer in Finnish women [7]. However, the occurrence of the c.687delT mutation in other populations has been difficult to confirm among non-BRCA1/2 hereditary breast cancer patients from the UK [13] and France [14]. Similarly the deletion was not detected in our previous study among Polish non-selected breast cancer patients [11], which is in agreement with results of the current study.…”

Section: Discussionmentioning

confidence: 99%

The MRN protein complex genes: MRE11 and RAD50 and susceptibility to head and neck cancers

et al. 2013

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BackgroundThe members of MRE11/RAD50/NBN (MRN) protein complex participates in DNA double-strand break repair and DNA-damage checkpoint activation. We have previously shown that the p.I171V NBN gene mutation may contribute to the development of laryngeal cancer. This study tested the hypothesis that variants of the MRE11 and RAD50 genes, previously described as cancer risk factors, predispose to increased susceptibility to head and neck cancer.FindingsIn this study we analyzed the RAD50 and MRE11 genes in 358 patients: 175 with a single laryngeal cancer (LC), 115 with multiple primary tumors but one malignancy (primary or second) localized in the larynx (MPT-LC), 68 patients with multiple primary tumors localized in the head or neck (MPT) and 506 controls. No carriers of previously reported mutation in the MRE11 or RAD50 gene (particularly the pathogenic c.687delT) were detected in the present study. We identified the p.V127I variant (2/175 LC, 2/506 controls; OR=2.91; 95% CI 0.41-20.85) and p.V315L variant (2/115 MPT-LC, 1/506 controls; OR=8.96; 95% CI 0.81-99.68) of the RAD50 gene.ConclusionsOur data indicated that previously described common genetic variations in the MRE11 and RAD50 genes do not contribute to an increased risk of laryngeal cancer and second primary tumors localized in the head and neck. Prospective studies with larger groups of patients may reveal the possible impact of these genes in tumor occurrence.

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

Cited by 12 publications

References 9 publications

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

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

The MRN protein complex genes: MRE11 and RAD50 and susceptibility to head and neck cancers

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

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