Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer

Zhang, X.; Pageon, Laura R.; Post, Sean M.

doi:10.1038/onc.2014.377

Cited by 7 publications

(9 citation statements)

References 46 publications

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“…The results from all four meta‐analyses came to a same conclusion: the variant G allele of the polymorphism was associated with an increased colorectal cancer risk among Asians but not Caucasians. The risk increment was consistent with the observation that the G allele has an enhanced affinity towards the Sp1 transcription factor, which results in an increased MDM2 transcription and eventually a higher protein level . This effectively attenuates the tumor suppressor functions of p53, leading to a heightened risk of cancer.…”

Section: Genes Encoding Transcription Factors and Related Proteinssupporting

confidence: 86%

“…The risk increment was consistent with the observation that the G allele has an enhanced affinity towards the Sp1 transcription factor, which results in an increased MDM2 transcription and eventually a higher protein level. 141 This effectively attenuates the tumor suppressor functions of p53, leading to a heightened risk of cancer. The MDM2 c.14+309 T>G polymorphism can therefore serve as a potential biomarker for predicting predisposition to colorectal cancer among Asians.…”

Section: Mdm2mentioning

confidence: 99%

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Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition

Tan

2018

The Journal of Gene Medicine

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Colorectal cancer is a leading form of cancer in both males and females. Early detection of individuals at risk of colorectal cancer allows proper treatment and management of the disease to be implemented, which can potentially reduce the burden of colorectal cancer incidence, morbidity and mortality. In recent years, the role of genetic susceptibility factors in mediating predisposition to colorectal cancer has become more and more apparent. Identification of high-frequency, low-penetrance genetic polymorphisms associated with the cancer has therefore emerged as an important approach which can potentially aid prediction of colorectal cancer risk. However, the overwhelming amount of genetic epidemiology data generated over the past decades has made it difficult for one to assimilate the information and determine the exact genetic polymorphisms that can potentially be used as biomarkers for colorectal cancer. This review comprehensively consolidates, based primarily on results from meta-analyses, the recent progresses in the search of colorectal cancer-associated genetic polymorphisms, and discusses the possible mechanisms involved.

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Section: Genes Encoding Transcription Factors and Related Proteinssupporting

confidence: 86%

Section: Mdm2mentioning

confidence: 99%

Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition

Tan

2018

The Journal of Gene Medicine

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“… 19 In vivo mouse models clearly demonstrated that the inactivation or loss of p53 stimulates tumorigenesis, whereas established tumors are disappeared or diminished after restoration of p53. 60 These data indicate that recovery of wild-type p53 function is a valid therapeutic approach, and the specific targeting of MDM2/MDMX to reactivate p53 is a viable anticancer strategy. 61 On the basis of this notion, structure-based drug design has led to the discovery of several MDM2 or MDMX antagonists that block the interactions between murine double minute (MDM) and p53, leading to p53 stabilization and activation for cancer treatment.…”

Section: Mechanisms Of Ring-type E3 Ligases In Crcmentioning

confidence: 93%

Functional significance and therapeutic implication of ring-type E3 ligases in colorectal cancer

et al. 2017

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Accumulative studies revealed that E3 ubiquitin ligases have important roles in colorectal carcinogenesis. The pathogenic mechanisms of colorectal cancer (CRC) initiation and progression are complex and heterogeneous, involving somatic mutations, abnormal gene fusion, deletion or amplification and epigenetic alteration, which may cause aberrant expression or altered function of E3 ligases in CRC. Defects of E3 ligases have been reported to be involved in the molecular etiology and pathogenesis of CRC. The aberrant expressed E3 ligases can function as either oncogenes or tumor suppressors depending on ubiquiting target substrates in CRC. Recently, considerable progress has been made in our understanding of the potential roles of E3 ligase-mediated ubiquitylation in colorectal carcinogenesis. There are mainly two subtypes of E3 ubiquitin ligases in humans, as defined by the presence of either a HECT domain or a RING finger domain on the basis of structural similitude. Most cancer-associated E3 ligases participate in regulating the cell cycle, apoptosis, gene transcription, cell signaling and DNA repair, the critical parts of CRC tumorigenesis. In this review, we have provided a comprehensive summary of abnormally expressed E3 ligases and their related pivotal mechanistic effects in CRC. In particular, we have highlighted the function of RING-type E3 ubiquitin enzymes in modulating cancer signaling pathways, immunity and tumor microenvironment in CRC development and progression; their mechanism(s) of action in CRC involving both ubiquitylation-dependent and ubiquitylation-independent effects; and the potential of RING E3 ligases as molecular biomarkers for predicting patient prognosis and as therapeutic targets in CRC. A better understanding of E3 ligase-mediated substrates' ubiquitylation involved in the development of CRC will provide new insights into the pathophysiology mechanisms of CRC, and unravel novel prognostic markers and therapeutic strategies for CRC.

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“…MDM2 SNP309 has been shown to modify this cancer risk in multiple cohorts of TP53 mutation carriers in an ageand gender-dependent manner. [22][23][24][25][26] Importantly, genetically engineered mouse models carrying either alleles of MDM2 SNP309 and a highly penetrant LFS p53 mutation demonstrated similar allele-specific differences in age-dependent cancer incidence. 26 Together, observations such as these suggest that SNPs could potentially modify ACC cancer risk.…”

Section: Introductionmentioning

confidence: 97%

“…[22][23][24][25][26] Importantly, genetically engineered mouse models carrying either alleles of MDM2 SNP309 and a highly penetrant LFS p53 mutation demonstrated similar allele-specific differences in age-dependent cancer incidence. 26 Together, observations such as these suggest that SNPs could potentially modify ACC cancer risk. Here, we studied two independent cohorts of ACC patients (paediatric and adult) to demonstrate that a SNP in a druggable gene and pathway significantly associates with ACC age-dependent incidence.…”

Section: Introductionmentioning

confidence: 97%

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence

et al. 2020

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BACKGROUND: Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist. METHODS: We analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits. RESULTS: A SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression. CONCLUSIONS: These results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.

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Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer

Cited by 7 publications

References 46 publications

Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition

Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition

Functional significance and therapeutic implication of ring-type E3 ligases in colorectal cancer

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence

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