MDM2 SNP309 polymorphism is associated with colorectal cancer risk

Wang, Weizhi; Du, Mulong; Gu, Dongying; Zhu, Lingjun; Chu, Haiyan; Tong, Na; Zhang, Zhengdong; Xu, Zekuan; Wang, Meilin

doi:10.1038/srep04851

Cited by 15 publications

(21 citation statements)

References 41 publications

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“…8,24,25 Likewise, animal studies confirm mice harboring two copies of the Mdm2 SNP309-G allele have an increased proclivity for developing sporadic cancers. 5 To directly evaluate the relationship between Mdm2 SNP309 and colon cancer, we injected cohorts of Mdm2 SNP309-G/G (G/G, n = 33) and Mdm2 SNP309-T/T (T/T, n = 33) mice weekly from 8 weeks of age until 20 weeks of age with 10 mg/kg of AOM and subsequently monitored mice for changes in morbidity and survival.…”

Section: Resultsmentioning

confidence: 95%

“…8,13,24,25 To directly examine the impact that the Mdm2 SNP309-G allele has on CRC, we generated two genetically engineered mouse models carrying the humanized MDM2 intron 1 harboring either the major (T) or minor (G) allelic variant. Importantly, the humanized intron used in this study is homozygous for the Mdm2 SNP285-G allelic variant, which does not interfere with Sp1 activities at the Mdm2 SNP309-G site.…”

Section: Discussionmentioning

confidence: 99%

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

2014

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A single-nucleotide polymorphism (SNP) in the promoter of the Mdm2 gene (Mdm2(SNP309-G)) results in an increased Mdm2 expression, partial attenuation of the p53 pathway and accelerated tumor development. Clinical case-control studies indicate the Mdm2(SNP309-)(G) allele associates with a significant increase in colorectal cancer (CRC) risk that is heightened in women, but the biological significance of this polymorphism has never been directly evaluated. To examine whether the Mdm2(SNP309-)(G) allele contributes to colorectal cancer, we generated cohorts of mice harboring either the G (minor allelic variant) or T (major allelic variant) allele and treated them with azoxymethane (AOM), a carcinogen that induces sporadic colorectal cancer. Mdm2(SNP309-G/G) mice displayed a significant reduction in survival following AOM treatment with more colonic lesions in a wider distribution throughout the lower and upper colon and an attenuated apoptotic response following exposure. AOM did not significantly induce stabilization of wild-type p53 or activate p53 downstream targets following AOM treatment, regardless of the genotype. Instead, Mdm2(SNP309-G/G) colons had significant changes in the expression of genes that regulate Mdm2 transcription (ERα and Sp1) as well as downstream targets of Mdm2. Together these results suggest the Mdm2(SNP309-)(G) allele significantly impacts CRC through mechanisms outside the p53 pathway.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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

2014

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“…Moreover, MDM2 overexpression, which results in p53 dysfunction, increases resistance to chemotherapy . Furthermore, in our previous study, we found that the MDM2 SNP309 polymorphism was a risk factor for colorectal cancers in Asians …”

Section: Introductionmentioning

confidence: 79%

“…[14][15][16][17] Furthermore, in our previous study, we found that the MDM2 SNP309 polymorphism was a risk factor for colorectal cancers in Asians. 18 However, few studies have reported on the predictive role of p53 signaling pathway SNPs in response to colorectal cancer chemotherapy. 19 The magnitude of the association between chemotherapy sensitivity and p53 signaling pathway SNPs has not been thoroughly elucidated to date.…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in p53 signaling pathway genes predict chemotherapy efficacy in colorectal cancer

et al. 2019

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Background The murine double minute‐2 gene ( MDM2 ) was originally identified as predicting chemotherapy efficacy. However, little is known regarding the association between single nucleotide polymorphisms (SNPs) in the p53 signaling pathway and prognosis/chemotherapy sensitivity in colorectal cancer. Methods We analyzed the association between 111 SNPs in 22 p53 signaling pathway genes and both progression‐free survival (PFS) and disease control rate (DCR) using Cox regression and logistics regression analysis. The false discovery rate method was used for correction of multiple testing. Secondary structure was predicted by RNAfold. Expression qualitative trait locus analysis and mRNA expression differences were assessed using the GTEx and TCGA databases. Results We found that the rs747828 C allele of TP73 was significantly associated with reduced PFS (HR = 1.64, 95% CI = 1.27‐2.12, P = 2.00 × 10 −4 ) in the additive model. In the stratified analysis, the rs747828 C allele was significantly associated with both reduced PFS ( P = 1.40 × 10 −3 ) and DCR ( P = 1.82 × 10 −2 ) in oxaliplatin‐based chemotherapy. The secondary structure of TP73 was altered in response to different rs747828 genotypes. Although the rs747828 C allele was not associated with messenger RNA (mRNA) TP73 expression, it was significantly associated with increased mRNA TP73‐AS1 expression levels in sigmoid tissues. TP73 mRNA was significantly overexpressed in tumor tissues compared to adjacent normal tissues ( P = 2.36 × 10 −19 ). Conclusion Our findings indicate that functional genetic variants of TP73 mediate the response to chemotherapy in colorectal cancer.

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“…Such an approach will definitely need to dovetail with chemoprevention, identification of individuals/ families with genetic predispositions and comprehensive information on biomarkers for early diagnosis of cancer. Thus far, even PSA screening for prostate cancer (one of the most widely used programs) has not been an entirely successful clinical tool [20,21]. In a genotype screen, the SNP309 T>G polymorphism, which is located in the promoter region of MDM2 gene, was identified and reported to contribute to the risk of colorectal In another study using whole transcriptome sequencing, a novel RUNX1-RUNX1T1 pathway was identified to be upregulated in clear cell renal cell carcinoma and considered an important factor contributing to the etiology of this cancer type [22].…”

Section: Single Cell Genomics In Cancer Prevention and Treatmentmentioning

confidence: 99%

The Promise of Single Cell Omics for Onco-therapy

Azizi¹,

Clouthier

Wicha³

2014

J Mol Genet Med

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Despite extensive research effort and considerable progress, the "war on cancer" that president Nixon declared in 1971 has yet to be optimally integrated into cancer therapeutics and as such cancer remains a major medical challenge for oncologists. The dynamic and complex biology of tumor cells undergoing clonal evolution generates cells with diverse degrees of drug resistance and metastatic potential. This highlights the need to be able to access this clonal density in order to develop effective therapeutics. With this prospective, early phase single cell studies are vital for thoroughly interrogating tumor heterogeneity to uncover more about cancer cell biology and to explore new therapeutic targets leading to more successful treatments. Current evidence supports the notion that clonogenic cells within the tumor mass may potentially give rise to a population of cells with unique genomic, transcriptomic and proteomic features distinct from the rest of the tumor mass. This observation can explain drug resistance after an initial period of primary tumor response. Therefore, completely abrogating or at a minimum achieving long-term, durable control over cancer requires researchers and oncologists to employ a personalized medicine approach that includes both tumor and patient-associated variables to modify current therapeutic regimens. In this review we discuss the importance of omics and in particular single cell genomics which are increasingly promising given recently developed technology advancements to facilitate exploration of cellular heterogeneity and tumor complexity. Keywords: Cancer genomics; Single cell; Tumor heterogeneity; Oncology therapy The Combinatorial Nature of CancerCancer is a catch all term for a collection of many related, but discrete diseases that share some degree of commonality, but can no longer be considered a single disease [1]. Although tumors may initiate following malignant transformation of even a single normal cell, more probably continuous genetic mutations and gene expression alterations during tumor progression lead to a metastatic phenotype composed of multiple subsets of tumor cells with distinct characteristics. In fact, each of the genetic and epigenetic events that happen to the tumor cells after tumor initiation result in a disease that collectively is termed cancer. Yet each discrete cancer shares certain characteristics with other malignancies. In this context, malignancy of tumor cells increase as a result of the cumulative formation of a series of tumor clones. Multi-step Cancer DevelopmentThe six elements of the model of multi-step cancer development [2] including uncontrolled proliferation, growth suppressor inactivation, cell death resistance, replicative immortality, angiogenesis induction and acquisition of an invasive and metastatic phenotype should be considered when defining a novel therapeutic regimen to eradicate primary and metastatic disease. Furthermore, these elements are important considerations for successful cancer therapy in the context propo...

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MDM2 SNP309 polymorphism is associated with colorectal cancer risk

Cited by 15 publications

References 41 publications

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

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

Genetic variants in p53 signaling pathway genes predict chemotherapy efficacy in colorectal cancer

The Promise of Single Cell Omics for Onco-therapy

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