Tumour selection advantage of non-dominant negative P53 mutations in homozygotic MDM2-SNP309 colorectal cancer cells

Alazzouzi, Hafid; Suriano, Gianpaolo; Guerra, Ángel; Plaja, Alberto; Espín, Eloi; Armengol, Manel; Alhopuro, Pia; Velho, Sérgia; Shinomura, Yasuhisa; González-Aguilera, Juan J.; Yamamoto, Hiroyuki; Aaltonen, Lauri A.; Capellà, Gabriel; Peinado, Miguel A.; Seruca, Raquel; Arango, Diego

doi:10.1136/jmg.2006.042572

Cited by 26 publications

(33 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are also consistent with previous reports describing that alterations in HDM2 are usually mutually exclusive with regard to TP53 mutations (38). A recent report describes that the SNP309 interacts with p53 mutational status and finds that the G allele enriches for a non -dominant-negative p53 mutations (17). Due to the low number of G allele enrichments among TP53-mutated cases in our series not allowing further statistical analyses, the dominant-negative activity was not assigned and modeled in our experimental design.…”

Section: Resultssupporting

confidence: 82%

A Polymorphism in HDM2 (SNP309) Associates with Early Onset in Superficial Tumors, TP53 Mutations, and Poor Outcome in Invasive Bladder Cancer

Sänchez‐Carbayo¹,

Socci

Kirchoff

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The HDM2 gene represents one of the central nodes in the p53 pathway. A recent study reported the association of a single nucleotide polymorphism (SNP309) in the HDM2 promoter region with accelerated tumor formation in both hereditary and sporadic cancers. In this study, we aim to evaluate the SNP309 in bladder cancer and to link it to TP53 status. Experimental Design: SNP309 genotyping and TP53 mutation status were done on 141 bladder tumors and 8 bladder cancer cell lines using a RFLP strategy andTP53 genotyping arrays, respectively. Transcript profiling of a subset of cases (n = 41) was done using oligonucleotide arrays to identify genes differentially expressed regarding their SNP309 status. Results: Of 141 bladder tumors analyzed, 36.9% displayed the SNP309 wild-type (WT; T/T) genotype, whereas 11.3% were homozygous (G/G) and 51.8% were heterozygous (T/G) cases. Patients with superficial disease and the G/G genotype had an earlier age on onset than those with the T/G or T/T genotypes (P = 0.029). Tumors with SNP309 WT genotype significantly displayed TP53 mutations when compared with tumors harboring G/G or T/G genotypes (P < 0.05). SNP309 WT cases had a poorer overall survival than cases with G/G and T/G genotypes (P < 0.05).TP53 mutation status provided enhanced prognostic value (P < 0.001).Transcript profiling identified TP53 targets among those differentially expressed between tumors displaying G/G orT/G SNP309 versus WTcases. Conclusions: SNP309 is a frequent event in bladder cancer, related to earlier onset of superficial disease and TP53 mutation status. SNP309 genotypes were found to be associated with clinical outcome.The HDM2 gene is a transcriptional target of p53. It encodes a negative feedback regulator (p90-Hdm2) that binds to p53 and acts as an ubiquitin-ligase, targeting p53 to proteasomal degradation (1). The association of a single nucleotide polymorphism (SNP309) in the HDM2 promoter region with accelerated tumor formation in both hereditary and sporadic cancers has been studied by several groups (2 -24). As Hdm2 expression levels seem to be critical to a well-regulated p53 response, naturally occurring sequence variations in the HDM2 promoter may result in altered expression of the Hdm2, affecting p53 tumor suppression activity (2). In addition, the association of SNP309 to an early age of onset in cancer predisposition syndromes has also been reported (2, 3), although it has also been reported lack of evidence that the HDM2 SNP309 accelerates tumor development in carriers of known pathogenic germ-line mutations, such of BRCA1 (4). Several case-control studies of squamous head and neck tumors, breast, ovarian, lung, and colon carcinomas did not found either such correlation (6 -10, 12, 16).Bladder tumors are known to commonly harbor TP53 mutations and less frequently HDM2 amplifications (25 -31). Although the abrogation of normal p53 function may be one of the permissive events promoting proto-oncogene amplification, predisposition to gene amplification of HDM2 in uroth...

show abstract

Section: Resultssupporting

confidence: 82%

A Polymorphism in HDM2 (SNP309) Associates with Early Onset in Superficial Tumors, TP53 Mutations, and Poor Outcome in Invasive Bladder Cancer

Sänchez‐Carbayo¹,

Socci

Kirchoff

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…In 165 CRC patients with wild-type p53 in their tumors, women, but not men, who carried the G-allele of SNP309 in either the heterozygous or homozygous state, showed a significant 9-year average earlier age of tumor diagnosis (P ¼ 0.0013), reminiscent of the gender-specific difference seen in DLBCL patients. If the gender of the CRC patients was ignored, this difference was significantly smaller, similar to other published reports (Alhopuro et al, 2005;Sotamaa et al, 2005;Allazzouzi et al, 2006). That this gender-specific difference could be owing to genderspecific hormones was supported again by the enrichment of individuals carrying the G-allele in women diagnozed before the average age of menopause, compared to either women diagnosed after the average age of menopause or men, much like in DLBCL, STS and high ER þ IDC.…”

Section: Gender and The Estrogen Signaling Pathwaysupporting

confidence: 80%

“…This hypothesis has been supported by the work on MDM2 SNP309. As the initial publication (Bond et al, 2004), multiple studies have shown that the G-allele of MDM2 SNP309 is associated with the attenuation of the p53 pathway and an enhanced early onset of and increased risk for, tumorigenesis (Bougeard et al, 2006;Hong et al, 2005;Swinney et al, 2005;Allazzouzi et al, 2006;Bond et al, 2006a, b;Dharel et al, 2006;Lind et al, 2006;Menin et al, 2006;Ohmiya et al, 2006;Park et al, 2006;Ruijs et al, 2007;Zhang et al, 2006). Because modest changes in levels of other central nodes of the p53 pathway (e.g.…”

Section: Resultsmentioning

confidence: 99%

A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans

2007

View full text Add to dashboard Cite

Cancer biology finds itself in a post-genomic era and the hopes of using inherited genetic variants to improve prevention and treatment strategies are widespread. One of the largest types of inherited genetic variation is the single nucleotide polymorphism (SNP), of which there are at least 4.5 million. The challenge now becomes how to discover which polymorphisms alter cancer in humans and how to begin to understand their mechanism of action. In this report, a series of recent publications will be reviewed that have studied a polymorphism in the p53 tumor suppressor pathway, MDM2 SNP309. These reports have lent insights into how germline genetic variants of the p53 pathway could interact with gender, environmental stresses and tumor genetics to affect cancer in humans. Importantly, these observations have also exposed potential nodes of intervention, which could prove valuable in both the prevention and treatment of this disease in humans.

show abstract

“…The selected study characteristics were summarized in Table 1. All studies were case-control studies, including eight breast cancer studies, six lung cancer (14,15,(18)(19)(20)31), but two of them did not present MDM2 SNP309 genotype distributions according to the p53 mutation status (15,20). Cases in most of the studies were histologically diagnosed, and three studies obtained DNA from tumor tissue of breast cancer (15), colorectal cancer (19), and uterine leiomyosarcoma (13).…”

Section: Resultsmentioning

confidence: 99%

MDM2 Promoter Polymorphism SNP309 Contributes to Tumor Susceptibility: Evidence from 21 Case-Control Studies

Jin

Wang

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

100

102

View full text Add to dashboard Cite

Since the identification of a well-characterized functional polymorphism named SNP309 in MDM2, abundant studies were published in the last 2 years to evaluate the association between SNP309 and tumor risk in diverse populations. However, the results remain conflicting rather than conclusive. Because a single study may have been underpowered to detect the effect of low-penetrance genes, a quantitative synthesis to accumulate data from different studies may provide better evidence on the association of genetic variant with tumor susceptibility. We conducted a metaanalysis on 14,770 cases with different tumor types and 14,524 controls from 25 published case-control studies to estimate the effect of SNP309 on tumor risk, as well as to quantify the potential between-study heterogeneity. We found that variant homozygote 309GG was associated with a significantly increased risk of all types of tumors [homozygote comparison: odds ratio (OR), 1.17, 95% confidential interval (95% CI), 1.04-1.33, P = 0.0002 for heterogeneity test; recessive model comparison: OR, 1.15, 95% CI, 1.03-1.28, P = 0.0005 for heterogeneity test]. Tumor type and ethnicity contributed to the substantial heterogeneity (69.5% for homozygote comparison and 77.2% for recessive model comparison). The analyses suggest that MDM2 SNP309 serves as a low-penetrance susceptibility tumor marker. Further large studies incorporate quantitative detection of different p53-responsible environmental stresses, p53 mutation status, and also functional genetic variants in p53-MDM2 -related genes are warranted. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2717 -23)

show abstract

Tumour selection advantage of non-dominant negative P53 mutations in homozygotic MDM2-SNP309 colorectal cancer cells

Abstract: MDM2-SNP309 favours tumour selection of non-dominant negative P53 mutations in CRC, which also show an earlier age of tumour onset.

Cited by 26 publications

References 14 publications

A Polymorphism in HDM2 (SNP309) Associates with Early Onset in Superficial Tumors, TP53 Mutations, and Poor Outcome in Invasive Bladder Cancer

A Polymorphism in HDM2 (SNP309) Associates with Early Onset in Superficial Tumors, TP53 Mutations, and Poor Outcome in Invasive Bladder Cancer

A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans

MDM2 Promoter Polymorphism SNP309 Contributes to Tumor Susceptibility: Evidence from 21 Case-Control Studies

Contact Info

Product

Resources

About