The association between the T309G polymorphism of the MDM2 gene and sensitivity to anticancer drug is dependent on the p53 mutational status in cellular models

Faur, Nicolas; Araud, L; Laroche-Clary, Audrey; Kanno, Jun; Toutain, Jérôme; Yamori, Takao; Robert, Jacques; Morvan, Valérie Le

doi:10.1038/sj.bjc.6605096

Cited by 13 publications

(5 citation statements)

References 31 publications

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“…We observed a higher frequency of MDM2, but not MDM2-C, tumors in Japanese patients, compared to White and Native Hawaiian patients (Table 2). Interestingly, several studies have found interactions between the MDM2 SNP309 genotype and p53-pathway status and breast cancer survival [44][45][46]. Similar interactions may contribute to the association differences that we are observing for the different racial/ethnic groups in our study.…”

Section: Discussionsupporting

confidence: 78%

MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population

Loo

Gao

Shvetsov

et al. 2018

Breast Cancer Res Treat

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Purpose: To examine the association between expression of mutant p53 (mtp53), full length MDM2 (MDM2), and MDM2 isoform C (MDM2-C) and survival in multiethnic breast cancer patients. Method: A total of 787 invasive breast tumors included in a clinically-annotated multiethnic population-based tissue microarray (TMA) were screened utilizing commercially available antibodies to p53 and MDM2, and a newly developed monoclonal antibody recognizing MDM2-C. Results: Mutant p53 (mtp53) was more common in younger (<50 yrs) breast cancer patients. Among the 787 cases included in the study, mtp53, MDM2, and MDM2-C expression was not significantly associated with risk of overall or breast cancer-specific mortality. However when associations within individual racial/ethnic groups (White, Japanese, and Native Hawaiian) were examined, expression of MDM2-C was found to be associated with lower risk of breast cancerspecific mortality exclusively for White patients (HR=0.32, 95% CI: 0.15-0.69) and mtp53 expression was associated with higher overall mortality in Japanese patients (HR=1.63, 95% CI: 1.02-2.59). Also, Japanese patients positive for the joint expression of MDM2-C and mtp53 had a greater than 2-fold risk of overall mortality (HR=2.15, 95% CI 1.04-4.48); and White patients with positive MDM2-C and wild-type p53 expression (HR=0.28, 95% CI 0.08-0.96) were at lower risk of mortality when compared to patients negative for MDM2-C and wild-type p53 expression in their respective racial/ethnic group.

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Section: Discussionsupporting

confidence: 78%

MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population

Loo

Gao

Shvetsov

et al. 2018

Breast Cancer Res Treat

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“…Although a single 1992 report noted a point mutation of p53 in codon 158 of exon 5 in H226 cells (15), we and several other investigators have confirmed the wt status of p53 without a point mutation in codon 158 in the H226 line ( Supplementary Fig. S2) (16-18). We therefore transiently transfected a full length wt p53 into the Cet-R cells using a pC53-SN plasmid.…”

Section: Resultssupporting

confidence: 56%

p53 Modulates Acquired Resistance to EGFR Inhibitors and Radiation

et al. 2011

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There is presently great interest in mechanisms of acquired resistance to EGFR inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms we established EGFR inhibitor resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell cycle arrest, apoptosis and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.

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“…In addition, an earlier age at onset of tumors was seen in Li-Fraumeni patients carrying the rare MDM2 GG-genotype compared to the T-allele carriers [23,29]. Another study performed in human tumor cell lines showed that the MDM2 SNP309 gene polymorphism had a major impact on the sensitivity to DNA-interfering drugs, especially in TP53 non-mutated cell lines [30]. These data together seem to suggest, though to some extent in opposite directions, that additional genetic changes in the tumor might be required for MDM2 SNP309 to induce and/or accelerate tumor progression.…”

Section: Introductionmentioning

confidence: 94%

Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups

Broek

Broeks

Horlings

et al. 2011

Breast Cancer Res Treat

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The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair "TP53 response pathway". Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis <53 years, n = 295) with gene expression data available. Patients were classified in subgroups according to their tumor TP53 mutation status and three gene expression profiles; a TP53 mutation status expression signature, a PTEN/PI3K pathway signature and the 70-gene prognosis profile. Survival analyses were performed using Cox regression models adjusting for clinico-pathological characteristics and treatment. An increase in breast cancer-specific mortality was observed for carriers of the germline MDM2 SNP309 rare GG-genotype (range hazard ratios: 2-3) or TP53 R72P heterozygous GC-genotype (range hazard ratios: 1-2) compared to those having the common genotypes within subgroups of tumors displaying a "more aggressive phenotype" gene expression profile. There was no evidence of such an effect on survival within the TP53-mutated tumor group for TP53 R72P carriers but a suggestion of an effect for MDM2 SNP309 carriers (GG vs. TT-genotype HR 2.99, P = 0.06). These results indicate that common polymorphisms in specific pathways may add to the worse prognosis of patients with tumors in which these pathways are affected by somatic alterations.

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The association between the T309G polymorphism of the MDM2 gene and sensitivity to anticancer drug is dependent on the p53 mutational status in cellular models

Cited by 13 publications

References 31 publications

MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population

MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population

p53 Modulates Acquired Resistance to EGFR Inhibitors and Radiation

Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups

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