# DNA Repair Phenotype the Missing Link in Breast Cancer Risk Assessment

> **NIH NIH U01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $621,179

## Abstract

ABSTRACT
DNA repair is a crucial mechanism for maintaining genomic stability in cells. Defects in the DNA repair machinery
increase cell vulnerability to DNA-damaging agents and accumulation of mutations in the genome, and lead to
the development of various disorders including cancers. Studies that have measured DNA repair capacity (DRC),
including our own, have estimated a much higher risk of breast cancer (BC) (3-15-fold) than most other
established risk factors for BC, with the exception of highly penetrant mutations in genes like BRCA1 and BRCA2,
genes critical to DNA repair. Despite the strength of this association, no large-scale prospective studies of BC
exist. Even though some BC risk models include known mutations in DNA repair genes, genotype only partially
explains phenotype, and BC risk models currently do not include phenotypic DNA repair measures. The lack of
inclusion of a major risk factor – DRC – is likely the major reason that clinical BC risk models have only modest
performance - which makes it very challenging to target effective primary prevention options (e.g.,
chemoprevention) for the majority of women who are not known mutation carriers. Further, secondary prevention
options (e.g., onset, frequency, and method of BC screening by mammography or other supplemental methods)
could be targeted more efficiently if more accurate risk assessment existed. The main limitation of use of DRC
for targeted prevention has been the lack of a high-throughput DRC assay, in particular a phenotypic DRC assay,
for integration into cancer risk assessment. We have overcome this major gap by adapting our high-throughput,
fully-automated ɣ-H2AX assay system which was originally designed for assaying DNA double strand breaks
(DSB) in freshly-drawn blood for use with archival blood samples. We propose one of the largest prospective
studies estimating the effect of DSB repair using an enriched cohort (n=12,563) that spans the spectrum of
absolute BC risk. Using a nested case-control design within this cohort (699 cases, 1:1 match), we will measure
DSB-DRC in archival biospecimens collected at baseline (Aim 1a). We will optimize the assay protocol for
measuring DSB-DRC using fresh fingerstick blood and measure longitudinal changes in DSB-DRC in young
women (age <40 years) (Aim 1b) (n=100, 1-2 years apart). We will then comprehensively assess the
independent contribution of DSB-DRC over genetic and epigenetic alterations in DSB repair genes, and assess
and whether genetic and epigenetic changes interact with DSB-DRC in increasing BC risk (Aim 2). We will
investigate the clinical utility of DSB-DRC by quantifying the improvement in standard BC risk model performance
from its inclusion (Aim 3a), and evaluating the association between DSB-DRC and 5 year survival after BC
diagnosis (Aim 3b). Our study will provide essential empirical evidence from integrating functional assays into
population studies to accelerate targeted prevention options linked to aber...

## Key facts

- **NIH application ID:** 10215533
- **Project number:** 5U01ES029660-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** DAVID JONATHAN BRENNER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $621,179
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215533

## Citation

> US National Institutes of Health, RePORTER application 10215533, DNA Repair Phenotype the Missing Link in Breast Cancer Risk Assessment (5U01ES029660-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10215533. Licensed CC0.

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