A functionally significant SNP in TP53 and breast cancer risk in African-American women

Maureen E Murphy,Yang Feng ,Sue A Ingles,Song Yao,Jennifer J Hu,Clement Adebamowo,Leslie Bernstein,Katherine L Nathanson,Andrew F Olshan,Qiang Hu,Barbara Nemesure,Zheng Wang ,Jorge L Rodriguez-Gil,Sandra L Deming,Julie R Palmer,Temidayo O Ogundiran,Stefan Ambs,Dezheng Huo,Olufunmilayo I Olopade,Sonia Dolfi ,Chi Chen Hong ,Kathryn L Lunetta,Kim M Hirshfield,Susan M Domchek,Regina G Ziegler,Liu Q ,Song Liu,Michael F Press,Esther M John,Sarah J Nyante ,William J Blot,Christopher A Haiman,Christine B Ambrosone

doi:10.1038/s41523-017-0007-9

Abstract

A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08–2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

Highlights

The p53 tumor suppressor (TP53) holds distinction as the most frequently mutated gene in human cancer
We previously showed that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53, but exhibits a significant defect in cell death induced by cisplatin.[8]
Because of the strong functional significance of this variant, and it’s specificity to populations of African ancestry, it could play a role in the earlier npj Breast Cancer (2017) 5

Summary

Introduction

The p53 tumor suppressor (TP53) holds distinction as the most frequently mutated gene in human cancer. In addition to inactivating mutations in human cancer, there are a number of single-nucleotide polymorphisms (SNPs) in TP53, and in genes whose protein products regulate p53, MDM2, and MDM4; these SNPs modify TP53 (hereafter p53) pathway signaling, and can confer increased risk for cancer.[1,2,3] Of note, the proline 72 allele in TP53, and the G allele of SNP309 in MDM2, have previously been associated with increased breast cancer risk in pre-menopausal women.[4, 5] More than two decades ago, an inherited polymorphism in TP53 that converts the proline residue at amino acid 47 to a serine was reported in African Americans (Pro47Ser, rs1800371, G/ A).[6] We showed that the serine 47 (hereafter S47) variant has significantly impaired ability to induce programmed cell death in multiple human cell lines engineered to contain inducible human forms of WT p53 and S47 The Pro47Ser polymorphism appears to be restricted to African-descent populations at a minor allele frequency (MAF) of 1.6%, and is Received: 17 June 2016 Revised: 22 November 2016 Accepted: 9 January 2017

Methods

Results

Conclusion