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

Abstract

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...

Mdm2 Snp309 G allele displays high frequency and inverse correlation with somatic P53 mutations in hepatocellular carcinoma

“…In fact, numerous studies have shown that overexpression of MDM2 is an important event in carcinogenesis; in addition, MDM2 amplification occurs mostly in the absence of p53 mutation, supporting the concept that MDM2 amplification and p53 mutation are alternative mechanisms of p53 dysfunction [8,18,19]. In agreement with our hypothesis, a recent study shows that invasive bladder cancer patients with wild-type SNP309 (T/T) were prone to displaying p53 mutations [20].…”

Prognostic potential of the MDM2 309T>G polymorphism in stage I lung adenocarcinoma

“…The T/T genotype was associated with poor survival in patients with aggressive bladder cancer [27], in line with our observations. The cited authors concluded that p53 mutational status was of prognostic value, but, in this study, the p53 mutation levels did not differ significantly by MDM2 genotype (Table 3).…”

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

“…Support for the model has come from the association of MDM2 SNP309 with differences in the onset of, or the risk for, cancer, as well as survival (2,3,18). For example, earlier ages of onset associated with individuals possessing the G-allele have been demonstrated in softtissue sarcomas (1,19,20), lymphoma (21), leukemia (22), melanoma (23), head, neck, and oral squamous cell carcinomas (24,25), and cancers of the colon (26), breast (21,27,28), bladder (29), ovary (30), brain (31), and liver (32).…”