Abstract
BackgroundMDM4 is a negative regulator of p53 and cooperates with MDM2 in the cellular response to DNA damage. It is unknown, however, whether MDM4 gene alterations play some role in the inherited component of breast cancer susceptibility.MethodsWe sequenced the whole MDM4 coding region and flanking untranslated regions in genomic DNA samples obtained from 40 German patients with familial breast cancer. Selected variants were subsequently screened by RFLP-based assays in an extended set of breast cancer cases and controls.ResultsOur resequencing study uncovered two MDM4 coding variants in 4/40 patients. Three patients carried a silent substitution at codon 74 that was linked with another rare variant in the 5'UTR. No association of this allele with breast cancer was found in a subsequent screening of 133 patients with bilateral breast cancer and 136 controls. The fourth patient was heterozygous for the missense substitution D153G which is located in a less conserved region of the MDM4 protein but may affect a predicted phosphorylation site. The D153G substitution only partially segregated with breast cancer in the family and was not identified on additional 680 chromosomes screened.ConclusionThis study did not reveal clearly pathogenic mutations although it uncovered two new unclassified variants at a low frequency. We conclude that there is no evidence for a major role of MDM4 coding variants in the inherited susceptibility towards breast cancer in German patients.
Highlights
MDM4 is a negative regulator of p53 and cooperates with MDM2 in the cellular response to DNA damage
We conclude that there is no evidence for a major role of MDM4 coding variants in the inherited susceptibility towards breast cancer in German patients
The patient series had been used previously to determine the frequency of selected mutations in the BRCA1, ATM and CHEK2 genes [16,17,18,19,20] as well as some more common polymorphisms in candidate genes tested by the Breast Cancer Association Consortium [21,22,23]
Summary
MDM4 is a negative regulator of p53 and cooperates with MDM2 in the cellular response to DNA damage. It is unknown, whether MDM4 gene alterations play some role in the inherited component of breast cancer susceptibility. As part of a genome surveillance network, the tumour suppressor protein p53 becomes stabilized after DNA damage and modulates intracellular responses such as cell cycle arrest, DNA repair, senescence or apoptosis [1,2,3]. An MDM2-related protein, MDM4, has more recently emerged as another p53-interacting protein with a central role in the DNA damage response [7,8,9]. MDM4 is regarded a negative regulator of p53 and cooperates with MDM2 to antagonize p53 [8,9,10]. In response to DNA double strand breaks, MDM4 becomes phosphorylated by the ATM and Chk kinases in an ATM-dependent manner which leads to a switch from the degradation of p53 to the degradation of MDM4 and consecutive stabilization of p53 [9,1114]
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