Specific allelic variants of SNPs in the MDM2 and MDMX genes are associated with earlier tumor onset and progression in Caucasian breast cancer patients
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Marcus Bauer1, Eva Johanna Kantelhardt2,3, Thorsten Stiewe4,5,6, Andrea Nist4, Marco Mernberger4, Katharina Politt4, Volker Hanf7, Tilmann Lantzsch8, Christoph Uleer9, Susanne Peschel10, Jutta John11, Jörg Buchmann12, Edith Weigert13, Karl-Friedrich Bürrig14, Claudia Wickenhauser1, Christoph Thomssen2, Frank Bartel1,* and Martina Vetter2,*
1Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
2Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
3Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
4Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
5Genomics Core Facility, Philipps-University, Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
6Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
7Department of Gynaecology, Hospital Fuerth, Fuerth, Germany
8Department of Gynaecology, Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany
9Onkologische Praxis Uleer, Hildesheim, Germany
10Department of Gynaecology, St. Bernward Hospital, Hildesheim, Germany
11Department of Gynaecology, Helios Hospital Hildesheim, Hildesheim, Germany
12Institute of Pathology, Hospital Martha-Maria, Halle (Saale), Germany
13Institute of Pathology, Hospital Fuerth, Fuerth, Germany
14Institute of Pathology Hildesheim, Hildesheim, Germany
*Co-senior authors and contributed equally to this work
Frank Bartel, email: firstname.lastname@example.org
Keywords: p53; mutation; tumor suppression; breast cancer; single nucleotide polymorphism
Received: September 18, 2018 Accepted: February 15, 2019 Published: March 08, 2019
Background: Genetic factors play a substantial role in breast cancer etiology. Genes encoding proteins that have key functions in the DNA damage response, such as p53 and its inhibitors MDM2 and MDMX, are most likely candidates to harbor allelic variants that influence breast cancer susceptibility. The aim of our study was to comprehensively analyze the impact of SNPs in the TP53, MDM2, and MDMX genes in conjunction with TP53 mutational status regarding the onset and progression of breast cancer.
Methods: In specimen from 815 breast cancer patients, five SNPs within the selected genes were analyzed: TP53 – Arg72Pro (rs1042522), MDM2 – SNP285 (rs2279744), SNP309 (rs117039649); MDMX – SNP31826 (rs1563828), and SNP34091 (rs4245739). Classification of the tumors was evaluated by histomorphology. Subtyping according hormone receptor status, HER2-status and proliferation rate enabled provision of the clinico-pathological surrogate of intrinsic subtypes.
Results: The homozygous C-allele of MDM2 SNP285 was significantly associated with a younger age-at-diagnosis of 44.2 years, in contrast to G/G- and G/C-patients (62.4, 62.7 yrs., respectively; p = 0.0007; log-Rank-test). In contrast, there was no difference regarding the age-at-diagnosis for patients with the respective genotypes of MDM2 SNP309 (p = 0.799; log-Rank-test). In patients with estrogen receptor (ER)-positive and TP53-mutated tumors, however, the T/T-genotype of the MDM2 SNP309 was significantly associated with an earlier average age-at-diagnosis compared with T/G+G/G-patients (53.5 vs. 68.2 yrs; p = 0.002; log-Rank-test). In the triple-negative subgroup, the G/G-patients had an average age-at-diagnosis of 51 years compared with 63 years for SNP309T carriers (p = 0.004; log-Rank-test) indicating a susceptibility of the G/G genotype for the development of triple negative breast cancer. Patients with the A/A-genotype of MDMX SNP31826 with ER-negative tumors were diagnosed 11 years earlier compared with patients and ER-positive tumors (53.2 vs. 64.4 yrs; p = 0.025, log-Rank-test). Furthermore, in luminal B-like patients (HER2-independent) the C/C-genotype of MDMX SNP34091 was significantly correlated with a decreased event-free survival compared with the A/A-genotype (p < 0.001; log-Rank-test).
Conclusions: We showed that SNPs in the MDM2 and MDMX genes affect at least in part the onset and progression of breast cancer dependent on the ER-status. Our findings provide further evidence for the distinct etiological pathways in ER-negative and ER-positive breast cancers.
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