Dataset Information

Effects of MDM2, MDM4 and TP53 codon 72 polymorphisms on cancer risk in a cohort study of carriers of TP53 germline mutations.

ABSTRACT:

Background

Previous studies have shown that MDM2 SNP309 and p53 codon 72 have modifier effects on germline P53 mutations, but those studies relied on case-only studies with small sample sizes. The impact of MDM4 polymorphism on tumor onset in germline mutation carriers has not previously been studied.

Methodology/principal findings

We analyzed 213 p53 germline mutation carriers including 168(78.9%) affected with cancer and 174 who had genotypic data. We analyzed time to first cancer using Kaplan-Meier and Cox proportional hazards methods, comparing risks according to polymorphism genotypes. For MDM2 SNP309, a significant difference of 9.0 years in the average age of cancer diagnosis was observed between GG/GT and TT carriers (18.6 versus 27.6 years, P = 0.0087). The hazards ratio was 1.58 (P = 0.03) comparing risks among individuals with GG/GT to risk among TT, but this effect was only significant in females (HR = 1.60, P = 0.02). Compared to other genotypes, P53 codon 72 PP homozygotes had a 2.24 times (P = 0.03) higher rate for time to develop cancer. We observed a multiplicative joint effect of MDM2 and p53 codon72 polymorphism on risk. The MDM4 polymorphism had no significant effects.

Conclusions/significance

Our results suggest that the MDM2 SNP309 G allele is associated with cancer risk in p53 germline mutation carriers and accelerates time to cancer onset with a pronounced effect in females. A multiplicative joint effect exists between the MDM2 SNP309 G allele and the p53 codon 72 G allele in the risk of cancer development. Our results further define cancer risk in carriers of germline p53 mutations.

SUBMITTER: Fang S

PROVIDER: S-EPMC2877078 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effects of MDM2, MDM4 and TP53 codon 72 polymorphisms on cancer risk in a cohort study of carriers of TP53 germline mutations.

Fang Shenying S Krahe Ralf R Lozano Guillermina G Han Younghun Y Chen Wei W Post Sean M SM Zhang Baili B Wilson Charmaine D CD Bachinski Linda L LL Strong Louise C LC Amos Christopher I CI

PloS one 20100526 5

<h4>Background</h4>Previous studies have shown that MDM2 SNP309 and p53 codon 72 have modifier effects on germline P53 mutations, but those studies relied on case-only studies with small sample sizes. The impact of MDM4 polymorphism on tumor onset in germline mutation carriers has not previously been studied.<h4>Methodology/principal findings</h4>We analyzed 213 p53 germline mutation carriers including 168(78.9%) affected with cancer and 174 who had genotypic data. We analyzed time to first canc ...[more]

PMID: 20520810

Similar Datasets

Project description:BackgroundNon-melanoma skin cancers are one of the most common human malignancies accounting for 2-3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas.MethodsWe studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism).ResultsWe found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R.ConclusionsThese studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations.

Dataset Information

Effects of MDM2, MDM4 and TP53 codon 72 polymorphisms on cancer risk in a cohort study of carriers of TP53 germline mutations.

Background

Methodology/principal findings

Conclusions/significance

Publications

Effects of MDM2, MDM4 and TP53 codon 72 polymorphisms on cancer risk in a cohort study of carriers of TP53 germline mutations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets