# Germline Genetic Modifiers of Radiation Response

> **NIH NIH R21** · SRI INTERNATIONAL · 2023 · $401,125

## Abstract

Approximately 50% of cancer patients receiving ionizing radiation suffer from radiation-induced normal tissue
injury that significantly affects quality of life and presents potentially life-threatening consequences in 5-10% of
the cases. Due to a large range of interpatient variability, the amount of radiation delivered to all patients is
largely guided by the tolerance of more radiosensitive individuals. Significant associations with biological genetic
determinates of interpatient variability to radiation responses from alleles with differing frequencies by population
ancestry will form the basis of our study. A better understanding of genetic factors that might contribute to a
deterministic radiation response would mitigate unwanted medical complications. The a priori identification of
genetic variants associated with increased radiation damage would be immensely useful for optimizing radiation
dose through predictive screening to allow creation of novel patient cohorts. We will use an in vitro approach and
apply genomics, transcriptomics, and functional modeling towards advanced determination of individual
genotypes most at risk for enhanced radiation sensitivity. An in-house panel of 100 normal-tissue derived
epithelial cell cultures from prostate and breast cancer patients will be used with exposure to ionizing irradiation.
A focus on individuals with differing genetic ancestry will be used for this purpose. Radiation response will be
quantified individually and in groups as continuous variables dependent on genetic variants and gene expression
following radiation exposure in association with statistical modeling to find genetic loci and epistatic SNP-SNP
interactions. In order to enlarge the scope and clinical relevance of our study, we will correlate our findings to
previously acquired germline DNA samples from patients treated with radiation with available clinical data as
well as radiation toxicity scores. The specific aims are: 1) to quantify the association of interpatient radiation
resistance and sensitivity with polygenic exome coding germline variants and gene expression using a radiation
associated senescence-associated secretory phenotype that is associated with pro-inflammatory cytokines and
2) screen DNA samples from radiation therapy patients with known toxicity scores and perform preliminary
functional testing to modulate radiation sensitivity in vitro for germline radiation associated variants. The results
of this proposal will provide a novel platform to screen for predictive variants in animal models and patients. This
will bring us one step closer to genomically guided radiation treatment and enable the investigation novel
mechanisms involved in radiation sensitivity.

## Key facts

- **NIH application ID:** 10741022
- **Project number:** 1R21CA274598-01A1
- **Recipient organization:** SRI INTERNATIONAL
- **Principal Investigator:** John Tyson McDonald
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $401,125
- **Award type:** 1
- **Project period:** 2023-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741022

## Citation

> US National Institutes of Health, RePORTER application 10741022, Germline Genetic Modifiers of Radiation Response (1R21CA274598-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10741022. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*