# Integrating Clues from the Somatic Genome in the Search for Rare Germline Cancer Susceptibility Variants

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $188,169

## Abstract

Project Summary/Abstract
It is well-established that human cancer has a substantial heritable component. However, studies have thus far
only been able to pinpoint a portion of the germline contribution. The hypothesis underpinning this proposal is
that genes and alleles that contribute to cancer susceptibility may be revealed using clues from the somatic
genome. Specifically, the focus of the project will be to develop a battery of statistical tests that will query large
sequencing data sets from patient paired tumor-normal genomes for signals of synergy between the genomic
variants in the two genomes. As part of the proposed work, the project will focus on myeloid malignancy to
demonstrate the system's efficacy. Toward this end, the project will pursue three Specific Aims:
1. Develop and apply statistical tests to paired whole-exome data from thousands of myeloid malignancy
 patients to identify genes/alleles that show signals of germline-somatic synergy.
 a) Query for genes in which germline and somatic events co-occur statistically frequently
 b) Query for genes in which germline and somatic events are statistically mutually exclusive
 c) Identify genes in which disruptive germline alleles are preferentially promoted over wild-type in
 chromosomal allelic imbalance events
2. Query germline DNA and tumor expression data for genes expressing the variant germline allele over
 wild-type in the tumor.
3. Expand findings in Aims 1 and 2 to a case-control study.
Large in-house, public, and collaborator genomic data sets from thousands of patients will be used to statistically
assess germline-somatic synergy. Genes showing such signals of synergy will then be subjected to a large case-
control study, under the hypothesis that the genes/alleles identified using clues from the somatic genome will
emerge as disease susceptibility loci.
 Ultimately, identifying inherited risk variants would have profound implications for diagnostics, clinical
management, and counseling. A panel of known susceptibility variants could be incorporated into screening
assays, which would serve as tools to inform physicians and their patients of elevated risk. This could result in a
higher level of surveillance, enabling early detection and more informed counselling for families carrying the risk
variants. Additionally, researchers would have a better picture of the gene and pathway disruptions that lead to
tumor development and resistance, eventually having the potential of finding new druggable targets for these
diseases, yielding new therapeutics.

## Key facts

- **NIH application ID:** 10159876
- **Project number:** 5R21CA249138-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Thomas Louis LaFramboise
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $188,169
- **Award type:** 5
- **Project period:** 2020-05-06 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159876

## Citation

> US National Institutes of Health, RePORTER application 10159876, Integrating Clues from the Somatic Genome in the Search for Rare Germline Cancer Susceptibility Variants (5R21CA249138-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10159876. Licensed CC0.

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