Skip to main content
An official website of the United States government
Grant Details

Grant Number: 5R01CA253450-03 Interpret this number
Primary Investigator: Troester, Melissa
Organization: Univ Of North Carolina Chapel Hill
Project Title: P53, DNA Repair Imbalance, and Immune Response in Breast Cancer Mortality Disparities
Fiscal Year: 2023


Abstract

PROJECT SUMMARY/ABSTRACT Genome stability is determined by multiple DNA repair pathways, including both error-prone and error-free mechanisms. Mutations can be caused by inactivation of DNA repair pathways (e.g. BRCA1 defects) or by pathological activation of error-prone repair. The tumor suppressor p53 has pleiotropic effects on this balance. It physically interacts with base excision repair (BER), modulates nucleotide excision repair (NER), and regulates mismatch repair (MMR). Wild type p53 may inhibit error prone, but not error-free non-homologous end joining (NHEJ), and can modulate homologous recombination (HR). Recently, new roles for p53 have been identified, such as a role in APOBEC3B activation. Many mechanistic studies have studied the complex roles of p53 in DNA repair, but few large-scale studies of human tumors have investigated p53 and DNA repair pathway function in human tumors, and even fewer have evaluated these relationships by race. A more refined understanding of the relationships between p53 loss, DNA repair, and mutational signatures is now possible due to: (1) the advent of mutational signatures, which can provide DNA evidence of the functional effects and balance across multiple error prone and error free DNA repair pathways; and (2) recent improvements in expression profiling from formalin-fixed paraffin embedded (FFPE) samples. These advances are important for understanding breast cancer mortality disparities because they enable broad scale study in population-based resources. Our previous population-based studies have shown that p53 mutations are more common in African American breast cancer patients (60% p53 mutant vs. 35% among white breast cancer patients). Furthermore, DNA repair is critical for response to chemotherapy, both due to direct effects of DNA repair on chemotherapy resistance, and indirect effects on activation of immune responses. The current project will use an integrative approach to evaluate p53-related DNA repair pathway irregularities in human tumors, measuring both RNA expression and mutational signatures (Aim 1a). Then, p53 loss and DNA repair imbalance will be evaluated in relation to immune activation using both RNA and protein-based, spatial assays of immune markers (Aim 1b). These analyses will leverage, the Carolina Breast Cancer Study (CBCS), a study of 3000 women with breast cancer that oversampled black women (50% black women, n=1500). To better understand the germline determinants of black-white differences in DNA repair, existing genome wide SNP data will be used to identify genetic variants linked with DNA repair imbalance and immune response (Aim 2). This investigation will identify key DNA repair and immune pathways, in context of p53 mutation status and race, that interact to cause cancer progression and chemoresistance. The elucidation of these pathways is a key underlying step in identifying clinical and public health interventions to reduce mortality disparities. 1



Publications

Diffsig: Associating Risk Factors with Mutational Signatures.
Authors: Park J.E. , Smith M.A. , Van Alsten S.C. , Walens A. , Wu D. , Hoadley K.A. , Troester M.A. , Love M.I. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2024-05-01; 33(5), p. 721-730.
PMID: 38426904
Related Citations

Patterns of chemotherapy receipt among patients with hormone receptor-positive, HER2-negative breast cancer.
Authors: Olsson L.T. , Hamilton A.M. , Van Alsten S.C. , Lund J.L. , Stürmer T. , Nichols H.B. , Reeder-Hayes K.E. , Troester M.A. .
Source: Breast cancer research and treatment, 2024 Feb; 204(1), p. 107-116.
EPub date: 2023-12-09.
PMID: 38070094
Related Citations

Diffsig: Associating Risk Factors With Mutational Signatures.
Authors: Park J.E. , Smith M.A. , Van Alsten S.C. , Walens A. , Wu D. , Hoadley K.A. , Troester M.A. , Love M.I. .
Source: bioRxiv : the preprint server for biology, 2023-02-10; , .
EPub date: 2023-02-10.
PMID: 36798154
Related Citations

Incorporating RNA-based Risk Scores for Genomic Instability to Predict Breast Cancer Recurrence and Immunogenicity in a Diverse Population.
Authors: Hamilton A.M. , Van Alsten S.C. , Gao X. , Nsonwu-Farley J. , Calhoun B.C. , Love M.I. , Troester M.A. , Hoadley K.A. .
Source: Cancer research communications, 2023 Jan; 3(1), p. 12-20.
EPub date: 2023-01-05.
PMID: 36968228
Related Citations

RNA-Based Classification of Homologous Recombination Deficiency in Racially Diverse Patients with Breast Cancer.
Authors: Walens A. , Van Alsten S.C. , Olsson L.T. , Smith M.A. , Lockhart A. , Gao X. , Hamilton A.M. , Kirk E.L. , Love M.I. , Gupta G.P. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2022-12-05; 31(12), p. 2136-2147.
PMID: 36129803
Related Citations

The Landscape of Immune Microenvironments in Racially Diverse Breast Cancer Patients.
Authors: Hamilton A.M. , Hurson A.N. , Olsson L.T. , Walens A. , Nsonwu-Farley J. , Kirk E.L. , Abdou Y. , Downs-Canner S.M. , Serody J.S. , Perou C.M. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2022-07-01; 31(7), p. 1341-1350.
PMID: 35437570
Related Citations

Prognostic significance of RNA-based TP53 pathway function among estrogen receptor positive and negative breast cancer cases.
Authors: Hurson A.N. , Abubakar M. , Hamilton A.M. , Conway K. , Hoadley K.A. , Love M.I. , Olshan A.F. , Perou C.M. , Garcia-Closas M. , Troester M.A. .
Source: NPJ breast cancer, 2022-06-14; 8(1), p. 74.
EPub date: 2022-06-14.
PMID: 35701440
Related Citations

Quantitative analysis of breast cancer tissue composition and associations with tumor subtype.
Authors: Olsson L.T. , Williams L.A. , Midkiff B.R. , Kirk E.L. , Troester M.A. , Calhoun B.C. .
Source: Human pathology, 2022 May; 123, p. 84-92.
EPub date: 2022-02-23.
PMID: 35218811
Related Citations

TP53 Pathway Function, Estrogen Receptor Status, and Breast Cancer Risk Factors in the Carolina Breast Cancer Study.
Authors: Hurson A.N. , Abubakar M. , Hamilton A.M. , Conway K. , Hoadley K.A. , Love M.I. , Olshan A.F. , Perou C.M. , Garcia-Closas M. , Troester M.A. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2022 Jan; 31(1), p. 124-131.
EPub date: 2021-11-04.
PMID: 34737209
Related Citations

Gene-Level Germline Contributions to Clinical Risk of Recurrence Scores in Black and White Patients with Breast Cancer.
Authors: Patel A. , García-Closas M. , Olshan A.F. , Perou C.M. , Troester M.A. , Love M.I. , Bhattacharya A. .
Source: Cancer research, 2022-01-01; 82(1), p. 25-35.
EPub date: 2021-10-28.
PMID: 34711612
Related Citations

Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non-Muscle-Invasive Bladder Cancer.
Authors: Damrauer J.S. , Roell K.R. , Smith M.A. , Sun X. , Kirk E.L. , Hoadley K.A. , Benefield H.C. , Iyer G. , Solit D.B. , Milowsky M.I. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2021-08-15; 27(16), p. 4599-4609.
EPub date: 2021-06-11.
PMID: 34117034
Related Citations

DeCompress: tissue compartment deconvolution of targeted mRNA expression panels using compressed sensing.
Authors: Bhattacharya A. , Hamilton A.M. , Troester M.A. , Love M.I. .
Source: Nucleic acids research, 2021-05-07; 49(8), p. e48.
PMID: 33524140
Related Citations




Back to Top