TP53 protein levels, RNA-based pathway assessment, and race among invasive breast cancer cases

Lindsay A Williams,Ashley M Fuller,Stephanie M Cohen,Ebonee N Butler,Joseph Geradts,Katherine A Hoadley,Emma H Allott,Melissa A Troester,Xuezheng Sun,Andrew F Olshan,Charles M Perou

doi:10.1038/s41523-018-0067-5

Abstract

Mutations in tumor suppressor TP53 have been inconsistently linked to breast cancer risk factors and survival. Immunohistochemistry (IHC) staining, a primary clinical means of TP53 mutation determination, only detects mutations that facilitate protein accumulation (e.g., missense mutations). RNA-based pathway methods capture functional status and may aid in understanding the role of TP53 function in racial disparities of breast cancer. TP53 status was assessed among invasive breast cancer cases from the Carolina Breast Cancer Study (CBCS) (2008–2013) using IHC and an established RNA-based TP53 signature (CBCS and The Cancer Genome Atlas (TCGA)). Frequency of TP53 status (IHC, RNA-based) was estimated in association with tumor characteristics, PAM50 intrinsic subtype, age, and race using relative frequency differences (RFDs) and 95% confidence intervals (95% CI) as the measure of association. Approximately 60% of basal-like tumors were TP53 protein positive (IHC), while nearly 100% were TP53 mutant-like (RNA). Luminal A tumors had low frequency of TP53 positivity (IHC: 7.9%) and mutant-like status (RNA: 1.7%). Mutant-like TP53 (RNA) was strongly associated with age ≤50 years, high tumor grade, advanced stage of disease, large tumor size, and basal-like and HER2 intrinsic subtypes. Black race was strongly associated with TP53 mutant-like status (RNA) (RFD: 24.8%, 95% CI: 20.5, 29.0) even after adjusting for age, grade, stage (RFD: 11.3%; 95% CI: 7.6, 15.0). Associations were attenuated and non-significant when measured by IHC. IHC-based TP53 status is an insensitive measurement of TP53 functional status. RNA-based methods suggest a role for TP53 in tumor prognostic features and racial disparities.

Highlights

In our study, nearly twice as many breast tumors were classified as sampled from a single tissue block, there could be some differences in the percent positivity for the whole tissue versus the averaged percent positivity that we calculated weighted by core cellularity
TP53 mutant-like when using RNA-based methods was observed among basal-like (RNA)-based gene expression compared to IHC, consistent with the observation that IHC
When using TCGA data to compare RNA-based classification of TP53 status to DNA-based mutation detection, mutation in TP53 resulting in accumulation of the protein within the nucleus

Summary

Introduction

TP53 mutations, which commonly include nonsense and frame shift alterations.[1] Mutations occur at much lower frequencies among Luminal A (12–23%) and Luminal B (15–29%) tumors[1,2,9,13,14,15] and are primarily missense mutations in form. TP53 mutation rates are higher among black women (25–32%) compared to white women (7–23%),[11,16] which may potentially help to explain existing racial disparities in breast cancer incidence and survival. Many previous studies that have evaluated race and TP53 status have used immunohistochemistry (IHC) methods that detect missense mutations resulting in protein accumulation.

Methods

Results

Conclusion