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. 2019 Mar 8;10(20):1975-1992.
doi: 10.18632/oncotarget.26768.

Specific allelic variants of SNPs in the MDM2 and MDMX genes are associated with earlier tumor onset and progression in Caucasian breast cancer patients

Marcus Bauer  1 , Eva Johanna Kantelhardt  2   3 , Thorsten Stiewe  4   5   6 , Andrea Nist  4 , Marco Mernberger  4 , Katharina Politt  4 , Volker Hanf  7 , Tilmann Lantzsch  8 , Christoph Uleer  9 , Susanne Peschel  10 , Jutta John  11 , Jörg Buchmann  12 , Edith Weigert  13 , Karl-Friedrich Bürrig  14 , Claudia Wickenhauser  1 , Christoph Thomssen  2 , Frank Bartel  1 , Martina Vetter  2
Affiliations

Specific allelic variants of SNPs in the MDM2 and MDMX genes are associated with earlier tumor onset and progression in Caucasian breast cancer patients

Marcus Bauer et al. Oncotarget. .

Abstract

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.

Keywords: breast cancer; mutation; p53; single nucleotide polymorphism; tumor suppression.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interests.

Figures

Figure 1
Figure 1. TP53 mutation spectrum according to intrinsic subtype
Mutation plot of somatic TP53 mutations (missense and nonsense mutations) in breast cancer. Abbr.: R110P – wild-type amino acid, codon, altered amino acid; Y107* - wild-type amino acid, altered codon, STOP; Bas – triple-negative (ductal); Her – HER2-positive (non-luminal); LuA – luminal A-like; LuB – luminal B-like.
Figure 2
Figure 2. Age-at-diagnosis of the first breast cancer for patients with the different genotypes of the TP53 Arg72Pro-SNP (G/G vs. G/C+C/C) and TP53 wild-type gene
Figure 3
Figure 3. Age-at-diagnosis of the first breast cancer for patients with the different genotypes of MDM2 SNP285 (G/G vs. G/C vs. C/C)
Figure 4
Figure 4. Age-at-diagnosis of the first breast cancer for patients with the A/A-genotype of MDMX SNP31826 and different ER-expression status
Figure 5
Figure 5
(A) Kaplan-Meier survival estimates for the event-free survival for patients with the different genotypes of the MDMX SNP31826 (G/G vs. G/A vs. A/A) in patients with luminal A-like subtype. (B) Kaplan-Meier survival estimates for the event-free survival for patients with the different genotypes of the MDMX SNP31826 (G/G vs. G/A vs. A/A) in patients with luminal B-like subtype (HER2-independent).
Figure 6
Figure 6
(A) Kaplan-Meier survival estimates for the event-free survival for patients with the different genotypes of the MDMX SNP34091 (A/A+A/C vs. C/C) in patients with luminal A-like subtype. (B) Kaplan-Meier survival estimates for the event-free survival for patients with the different genotypes of the MDMX SNP34091 (A/A+A/C vs. C/C) in patients with luminal B-like subtype (HER2-independent).
See this image and copyright information in PMC

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