# Defining the impact of mutant oncogene zygosity

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $404,888

## Abstract

PROJECT SUMMARY/ABSTRACT
Mutations in oncogenes encode proteins with gain-of-function biological properties that enhance fitness.
Historically, heterozygous mutations in oncogenes have been viewed as sufficient to induce cancer initiation or
promote cancer progression. However, oncogenic driver mutations often co-exist with extensive genomic gains
and losses. Yet, the interplay between these two fundamental properties of cancer genomes is poorly
understood. We recently showed that increased KRAS G12D copy number and subsequent loss of the WT
KRAS allele in leukemias leads to increased competitive fitness at the cost of increased MAP kinase pathway
dependence. In subsequent preliminary studies, we showed that zygosity changes targeting gain-of-function
oncogenic mutations are frequently selected for during cancer evolution and have prognostic and therapeutic
implications. These findings allude to broader growth suppressive effects of the WT allele on mutant oncogene
function and underscore the potential clinical importance of prospectively identifying for physicians and patients
changes in mutant oncogene zygosity within the context of precision oncology. Yet, without principled methods
for characterizing the extent and significance of oncogenic mutant allele imbalance, the gap in our
understanding of oncogene biology and therapy will widen. We therefore propose functional and translational
genomic investigations to test the hypothesis that changes in mutant oncogene zygosity dictates distinct tumor
biology and therapeutic sensitivities in cancer. In Aim 1, we leverage a cohort of 70,000 prospectively
sequenced cancer patients linked to detailed clinical and treatment annotation to establish the prevalence and
mechanisms of oncogenic mutant allele imbalance. We will identify the degree to which allelic imbalance
represents a predictive biomarker of therapeutic sensitivity and create a public resource for the scientific
community to foster broader mechanistic studies of mutant oncogene zygosity. Our preliminary data indicates
that competitive fitness drives the loss of WT RAS in approximately half of all RAS-mutant tumors. Thus, in
Aim 2 we utilize advances in single-cell characterization to define the origins of such serial genetic evolution,
establishing the chronology and fitness gains of independently arising molecular changes targeting the mutant
and wildtype KRAS alleles in single cells isolated from metastatic tumors of KRAS-mutant cancer patients.
Finally, in Aim 3 we use engineered cellular systems and patient-derived xenografts to study the tumor
suppressive effect of the commonly deleted WT allele of the estrogen receptor (ER) gene in ESR1-mutant ER+
metastatic breast cancers, extending this phenomenon beyond mutant RAS for the first time. In sum, the
proposed studies seek to establish the biological and clinical significance of changes to mutant oncogene
zygosity. Through the integration with our institutional clinical sequencing initia...

## Key facts

- **NIH application ID:** 9862406
- **Project number:** 1R01CA245069-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Sarat Chandarlapaty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,888
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9862406

## Citation

> US National Institutes of Health, RePORTER application 9862406, Defining the impact of mutant oncogene zygosity (1R01CA245069-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9862406. Licensed CC0.

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