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Updated: Jul 7, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Mutation analysis of the MDM4 gene in German breast cancer patients
Scarlett Reincke1, Lina Govbakh, Bettina Wilhelm
1Department of Gynaecology and Obstetrics, Hannover Medical School, Carl-Neuberg Str, 1, 30625 Hannover, Germany. doerk.thilo@mh-hannover.de
Background:
MDM4 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.
Methods:
We 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.
Results:
Our 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.
Conclusion:
This 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.
Insights
This study investigated MDM4 gene variants in familial breast cancer patients. No major role for MDM4 coding variants was found in inherited breast cancer susceptibility.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- MDM4 is a key negative regulator of p53, cooperating with MDM2 in DNA damage response.
- The role of MDM4 gene alterations in inherited breast cancer susceptibility remains unclear.
Purpose of the Study:
- To investigate the potential role of MDM4 gene alterations in the inherited component of breast cancer susceptibility.
- To identify and characterize MDM4 coding variants in German familial breast cancer patients.
Main Methods:
- Whole MDM4 coding region and flanking untranslated regions were sequenced in 40 German familial breast cancer patients.
- Selected variants were screened using RFLP-based assays in extended breast cancer cases and controls.
Main Results:
- Two MDM4 coding variants were identified in 4/40 patients: a silent substitution at codon 74 and a missense substitution D153G.
- The codon 74 variant, linked with a 5'UTR variant, showed no association with breast cancer in subsequent screening.
- The D153G substitution showed incomplete segregation with breast cancer in its family and was not found in further screening.
Conclusions:
- The study did not identify clearly pathogenic MDM4 mutations, uncovering only two new unclassified variants at low frequency.
- There is no evidence supporting a major role for MDM4 coding variants in the inherited susceptibility to breast cancer in the studied German population.
