# Mutational processes underlying tumor development in United States Veterans

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

Precision oncology aims to identify specific characteristics of a tumor, for example pathological or genomic
features, that allow selection of a treatment most likely to achieve success in a patient. While a large number of
single genomic alterations have been identified by large scale exome sequencing efforts, the National Cancer
Institute MATCH trial has revealed that targeting single pathologic exonic alterations achieve clinical benefit in
a minority of cancer patients. For example, lung cancer has the most molecularly directed targets; however,
work from multiple studies, including those conducted by the VA National Precision Oncology Program (NPOP)
has shown that therapeutic targets are identified in <30% of cases. Furthermore, therapeutic target rates are
lower in Veteran lung cancer compared to public data repositories like The Cancer Genome Atlas (TCGA).
Therefore, there is a critically urgent need to develop new tumor biomarkers for precision oncology.
One reason for the limited success of current precision oncology approaches is current clinical sequencing
tests focus mostly on point alterations (ie. BRAF, EGFR, BRCA1/2), which do not reflect the phenotypic
consequences of the mutational processes that initially caused the tumor. Mutational processes that
underlie human cancer leave mutational signatures in the genome that can be identified by whole
genome sequencing (WGS). Seminal work by the Sanger Institute has identified mutational patterns
indicative of defects in DNA replication and repair, mutagen exposures, and enzymatic modification of DNA.
Currently, 79 single base substitution, 11 doublet base substitution, and 18 insertion/deletion signatures have
been identified that reflect these mutational processes. In addition, patterns of copy number variants can
identify tumor genomes that have undergone doubling events, chromothripsis, kategsis, loss of heterozygosity,
and homologous recombination based DNA repair deficiency. The major published catalogs of tumor
mutational signatures include cancers predominantly from individuals of English descent from efforts in the
United Kingdom. Whether the same mutational signatures are at work in tumors from Veterans, and those
from diverse genetic ancestries, is currently unknown.
We hypothesize that mutational signatures will identify carcinogenic mechanisms resulting from
Veterans’ service-related environmental exposures, provide clinical utility in defining treatment for
Veteran cancer, and will inform further preventative measures to limit cancer-causing exposures. In
order to test this hypothesis, we propose two independent Specific Aims. In Specific Aim 1, we will perform
whole genome sequencing (WGS) on Veteran tumors and extract known and novel mutational signatures,
comparing the Veteran signatures to public data. In Specific Aim 2, we will determine the clinical utility of
mutational signatures. Our enterprise-wide team will leverage the resources of the National Precision Oncolog...

## Key facts

- **NIH application ID:** 10975944
- **Project number:** 5I01CX002709-02
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** MICHAEL J KELLEY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975944

## Citation

> US National Institutes of Health, RePORTER application 10975944, Mutational processes underlying tumor development in United States Veterans (5I01CX002709-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10975944. Licensed CC0.

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