# Diversity Supplement: Uncovering diverse genotype-phenotype relationships in prostate cancer

> **NIH NIH DP2** · FRED HUTCHINSON CANCER CENTER · 2022 · $268,726

## Abstract

Research Summary/Abstract
The sheer genetic heterogeneity and complexity of cancer has been laid bare by next-generation sequencing
studies of cancer genomes. A major challenge in the post-genomic era of cancer biology is to move beyond
descriptive analyses of genomic data and derive functional insights into the complex multigenic interactions
that produce complicated phenotypes associated with cancer evolution. Available experimental systems are
poorly-suited to address this problem in a systematic and expeditious manner as they generally lack scale,
throughput, economy, or biological relevance. We therefore propose the development of a next-generation
functional cancer genomics assay that overcomes these limitations and will be employed here to define
complicated genotype-to-phenotype relationships in contexts related to prostate cancer initiation and
progression. The assay combines the efficient delivery of random, compound genetic perturbations from
barcoded lentiviral libraries encoding gain-of-function and/or loss-of-function events; biological selection for a
cancer phenotype; and single-cell sequencing analysis to enumerate lentiviral barcodes for the massively
parallel association of genotype with phenotype. The major goal of this project is to apply and advance this
pioneering strategy to broadly advance our understanding of prostate cancer biology by characterizing
compound genetic interactions that (1) transform benign prostate epithelial cells to cancer and establish
distinct cancer subtypes, (2) induce neuroendocrine transdifferentiation of prostate cancer, and (3) promote
metastatic dissemination. If successful, these studies will characterize and prioritize the functional contributions
of multigenic networks to clinically relevant prostate cancer phenotypes. We will also establish multiple new,
genetically-defined mouse models of prostate cancer that will better recapitulate the genetic complexity of the
human disease. Finally, we anticipate that the next-generation functional cancer genomics strategy will be a
flexible and widely applicable experimental tool to rapidly interrogate complex genetic interactions and their
impacts on phenotype in many other cancers.

## Key facts

- **NIH application ID:** 10533682
- **Project number:** 3DP2CA271301-02S1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** John Kyung Lee
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $268,726
- **Award type:** 3
- **Project period:** 2021-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533682

## Citation

> US National Institutes of Health, RePORTER application 10533682, Diversity Supplement: Uncovering diverse genotype-phenotype relationships in prostate cancer (3DP2CA271301-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10533682. Licensed CC0.

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