Research Article: The combined survival effect of codon 72 polymorphisms and p53 somatic mutations in breast cancer depends on race and molecular subtype

Date Published: February 7, 2019

Publisher: Public Library of Science

Author(s): Shantel Hebert-Magee, Han Yu, Michael Behring, Trafina Jadhav, Chandrakumar Shanmugam, Andra Frost, Isam-Eldin Eltoum, Sooryanarayana Varambally, Upender Manne, Arun Rishi.

http://doi.org/10.1371/journal.pone.0211734

Abstract

The codon 72 polymorphism in the p53 gene relates to the risk of breast cancer (BC), but this relationship in racially diverse populations is not known. The present study examined the prognostic value of this polymorphism for African American (AA) and Caucasian (CA) BC patients separately and considered the confounding variables of molecular subtypes and somatic mutations in p53.

Tissue sections of BCs from 116 AAs and 160 CAs were evaluated for p53 mutations and genotyped for the codon 72 polymorphism. The relationships of phenotypes to clinicopathologic features were determined by χ2 analyses; patient survival was estimated by Kaplan-Meier univariate and Cox regression multivariate models in a retrospective cohort study design.

The proportion of single nucleotide polymorphism (SNP) 72 alleles differed for races. Many cancers of AAs were Pro/Pro, but most for CAs were Arg/Arg. A higher frequency of missense p53 mutations was evident for AAs. There was an interaction between the SNP allele and p53 mutations for AA women only. The proportion of women with both the Pro/Pro allele and a p53 somatic mutation was higher for AA than CA women. The interaction between missense p53 mutations and Pro/Pro had a negative effect on survival, particularly for AAs with luminal cancers.

For BCs, the survival effect of SNP72 combined with a p53 missense mutation is dependent on race and molecular subtype. Although such a mutation is a marker of poor prognosis, it is relevant to identify the variant Pro/Pro in the case of AAs, especially those with luminal subtypes of BC.

Partial Text

The reasons for racial differences in breast cancer (BC) incidence and mortality in the United States are not fully known. Non-Hispanic Caucasians (CAs) have a higher occurrence of BC; however, African Americans (AAs) have the poorest outcomes [1]. Although this disparity has been explained as primarily stemming from socioeconomic variations [2,3], the unequal survival among AA and CA patients is also linked to differing clinicopathologic characteristics [1,4,5]. Previous studies found that more biologically aggressive cancers contribute to the low survival rates for AA women relative to CA women [6]. Nonetheless, limited attention has been given to understanding the genetic and molecular basis for the racial discrepancy among women with BC.

Through this study, we demonstrated relationships between race, molecular subtype, SNP72, and somatic/missense mutations of p53 and survival for women with BC. In general, BCs of AA Pro/Pro patients were more susceptible to also exhibiting somatic/missense mutations in p53. This interaction between the germline p53 genotype and somatic/missense mutation was a predictor of survival for AAs based on molecular subtype. For cancers of AA TNBC women, the SNP 72 Arg/Arg variant along with p53 somatic mutation conveyed the poorest survival. However, for AA patients with luminal BCs, the SNP72 Pro/Pro variant and p53 somatic/missense mutation showed the worst survival.

 

Source:

http://doi.org/10.1371/journal.pone.0211734

 

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