Contrasting effects of an Mdm2 functional polymorphism on tumor phenotypes

Ortiz, Guadalupe J.; Li, Yanjie; Post, Sean M.; Pant, Vinod; Xiong, Shunbin; Larsson, Connie A.; El‐Naggar, Adel K.; Johnson, D. Gale; Lozano, Guillermina

doi:10.1038/onc.2017.344

Cited by 13 publications

(6 citation statements)

References 52 publications

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“…The fact that we observe opposite effects of SNP55 in endometrial-versus colon cancer may seem puzzling. However, this is in line with recent observations for other MDM2 promoter SNPs, indicating that their functional role and potential impact on cancer susceptibility is highly tissue specific (Ortiz et al 2018).…”

Section: Influence Of Mdm2 Snp55 On Age At Cancer Diagnosissupporting

confidence: 91%

Impact of MDM2 promoter SNP55 (rs2870820) on risk of endometrial and ovarian cancer

et al. 2021

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Background: While large GWAS analyses have not found convincing associations between MDM2 promoter SNP55 and gynaecological cancers, SNP55 is in linkage disequilibrium with two other functional SNPs in the same promoter, likely to obscure associations between single SNPs and cancer risk. Here, we assessed the impact of SNP55 on risk of endometrial and ovarian cancer, including sub-analyses stratified for other functional SNPs in the region. Material and methods: Using a custom LightSNiP assay, we genotyped SNP55 in two large hospitalbased cohorts of patients with ovarian (n ¼ 1,332) and endometrial (n ¼ 1,363) cancer and compared genotypes to healthy female controls (n ¼ 1,858). Results: Among individuals harbouring the SNP309TT genotype, the minor SNP55T-allele was associated with a reduced risk of endometrial (dominant model: OR ¼ 0.63; CI ¼ 0.45-0.88; p ¼ 0.01). Regardless of the genotype in neighbouring SNPs, the SNP55T-allele was also associated with a reduced risk of endometrial cancer before 50 years of age (dominant model: OR ¼ 0.56; CI ¼ 0.34-0.90; p ¼ 0.02). No association between SNP55 status and ovarian cancer risk was observed. Conclusions: MDM2 SNP55T-allele may correlate with reduced risk for endometrial cancer in a SNP309T-, but not SNP309G, context.

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Section: Influence Of Mdm2 Snp55 On Age At Cancer Diagnosissupporting

confidence: 91%

Impact of MDM2 promoter SNP55 (rs2870820) on risk of endometrial and ovarian cancer

et al. 2021

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“…The SP1 transcription factor preferably binds to the SNP309G variant and enhances the levels of Mdm2, ultimately dampening p53 activity and increasing cancer risk. However, additional studies in SNP309 mice challenged with environmental stress factors, such as low-dose ionizing radiation (IR), ultraviolet light, or benzo(a)pyrene, showed contrasting differences in vulner-ability to skin cancer risk (Ortiz et al 2018). In this context, SNP309G was bound by the E2F6 transcriptional inhibitor, which decreased Mdm2 levels and thus increased p53 levels and reduced the risk of skin cancer.…”

mentioning

confidence: 99%

SNPing away at mutant p53 activities

Ortiz

Lozano

2018

Genes Dev.

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A delicate balance in the levels of proteins that regulate the p53 tumor suppressor pathway exists such that subtle changes alter p53 tumor suppressor activity and cancer risk. Many single-nucleotide polymorphisms (SNPs) in the p53 pathway alter p53 transcriptional activity and are associated with cancer risk. In addition, some SNPs influence the gain-of-function (GOF) activities of mutant p53 through unknown mechanisms. In this issue of , Basu and colleagues (pp. 230-243) provide direct evidence that the presence of an R72 polymorphism enhances the GOF invasive and metastatic properties of mutant p53 by regulating interactions with PGC-1α, an important regulator of mitochondrial biogenesis and oxidative phosphorylation. The study culminates with evidence that R72 is associated with worse outcomes in human breast cancer.

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“…One other notable observation from this work is the high proportion of radiation-induced ovarian pathology that was identified in both genotypes, specifically ovarian carcinomas were identified in 32% of the female mice in this study. We have irradiated and followed several other cohorts of mice on different genetic backgrounds (C57BL/6 and BALB/c) and have not previously identified ovarian carcinomas (24, 38), suggesting that the 129S6/SvEvTac background may increase susceptibility to these cancers. Additionally, this is a spontaneous radiation-induced model that does not require the use of a cell-type specific Cre recombinase, and therefore circumvents concerns about targeting the correct cell of origin.…”

Section: Discussionmentioning

confidence: 99%

Daxx Functions Are p53-Independent In Vivo

Estrella

Pant

Chau

et al. 2018

Molecular Cancer Research

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Mutations in the death domain-associated protein (DAXX) have been recently identified in a substantial proportion of human pancreatic neuroendocrine tumors (PanNETs). Remarkably, however, little is known about the physiologic role(s) of DAXX despite studies suggesting potential functions. Most prominently, and supported by tumor sequencing data, DAXX functions in concert with alpha thalassemia/mental retardation X-linked (ATRX) as a histone chaperone complex for the H3.3 variant. Studies have also identified potential roles in apoptosis, transcription, and negative regulation of the p53 tumor suppressor pathway. Herein, a mouse modeling approach was used to specifically address the latter and no significant genetic interaction between Daxx and the p53 pathway was determined. The embryonic lethal phenotype of Daxx loss is not p53-dependent. In addition, Daxx heterozygosity does not sensitize mice to a sublethal dose of ionizing radiation or alter the survival or tumor phenotype of Mdm2 transgenic mice. However, the data support a tumor suppressor role for DAXX as low-dose ionizing radiation produced a higher proportion of carcinomas in Daxx heterozygous mice than wild-type controls. While DAXX has important functions, they are independent of an inhibitory role on the p53 tumor suppressor pathway..

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Contrasting effects of an Mdm2 functional polymorphism on tumor phenotypes

Cited by 13 publications

References 52 publications

Impact of MDM2 promoter SNP55 (rs2870820) on risk of endometrial and ovarian cancer

Impact of MDM2 promoter SNP55 (rs2870820) on risk of endometrial and ovarian cancer

SNPing away at mutant p53 activities

Daxx Functions Are p53-Independent In Vivo

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