# Elucidating Signatures of DNA Damage Response Alterations from Structural Variants in Human Cancer

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2024 · $36,983

## Abstract

Project Summary/Abstract
Despite substantial advances in the treatment and diagnosis of cancer over the past several decades, it
remains the second leading cause of death worldwide. Many current treatments have aimed at targeting
defects in DNA damage response (DDR) in cancer cells, including immunotherapy in mismatch repair deficient
cancers and PARP inhibitors in the context of homologous recombination deficiency. However, we are
currently unable to reliably determine which DDR defects are present in a given cancer sample, which
severely limits our ability to exploit these therapeutic vulnerabilities. Structural variants (SVs), or genomic
rearrangements formed as a product of aberrant double strand break repair, hold promise as biomarkers of
DDR state. Indeed, SVs affect a larger proportion of the cancer genome than any other form of genetic
alteration and have features that reflect their mechanism of formation. We hypothesize that novel
computational methods tailored to the complexity of SV features, as well as associations with newly
discovered SV features, will enable accurate assessment of variation in DDR across cancers. In Aim 1,
we will follow up on our laboratory’s recent discovery of significant discontinuous homology, or microhomeology
(MHe), in cancer SVs. First, we will engineer defined DDR defects in isogenic cell lines and assess their effects
on MHe. Then we will validate our in vitro data by assessing MHe patterns in human tumors that have
orthogonal evidence for DDR pathway defects. In Aim 2, we introduce Quant-HDP, a Bayesian non-parametric
generative algorithm based on the Hierarchical Dirichlet Process, which leverages complex modeling of SV
features to detect signatures (patterns of SVs) associated with specific biological processes. We will apply this
method to both publicly available cancer cohorts and internally sequenced pre- and post-chemotherapy
gliomas and endometrial cancers. We will then validate putative signature associations in isogenic cell lines. In
sum, this proposal makes use of untapped genomic features and sophisticated computational models to
distinguish between different DDR states and exposures, which has direct clinical implications.

## Key facts

- **NIH application ID:** 10993459
- **Project number:** 1F31CA287567-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Gregory Raskind
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,983
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993459

## Citation

> US National Institutes of Health, RePORTER application 10993459, Elucidating Signatures of DNA Damage Response Alterations from Structural Variants in Human Cancer (1F31CA287567-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10993459. Licensed CC0.

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