# Tissue-specific genetic interactions in cancer

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $499,355

## Abstract

Project Summary/Abstract
Advances in genome sequencing technologies over the past decade have provided a
comprehensive survey of the somatic mutations that contribute to cancer. In colorectal cancer
(CRC), the 3rd most common cause of cancer-related death in the United States, genome-wide
sequencing identified APC, KRAS, and PIK3CA as three of the most commonly mutated genes.
Nevertheless, large-scale, genome-wide sequencing efforts do not provide sufficient granularity
with respect to the interactions between mutant genes, especially at the level of specific mutant
alleles. Precision medicine, where a physician tailors a patient's therapy to the genes that are
mutated in his/her cancer, requires this level of understanding because the activation state of
oncogenic signaling pathways targeted by precision medicines is dependent upon the panoply
of genetic changes in a cancer rather than on mutations in individual genes. A case-in-point of
this concept relates to KRAS, in which activating missense mutations occur in 40% of CRCs.
Among those 40% of CRCs, the diversity of KRAS mutations is greater than in any other type of
cancer. We hypothesize that CRCs might select for KRAS alleles that are absent or rare in other
cancers because of a genetic interaction with mutant APC, which is nearly ubiquitous in CRC,
but rarer in other cancers. Moreover, aside from APC, the gene most commonly co-mutated
with KRAS is PIK3CA, yet PIK3CA mutations co-occur only with specific alleles of KRAS.
Building upon our expertise in studying the genetics of cancer using genetically engineered
mouse models, and based on our extensive preliminary analysis of animals engineered to
express mutant forms of K-Ras in the colon, we will perform an in-depth study of genetic
interactions between cancer genes in CRC. This work is separated into two specific aims: (1)
To determine the molecular mechanism underlying the genetic interaction between APC and
KRAS and (2) To understand why PIK3CA mutations occur preferentially with specific KRAS
alleles in CRC. In the end, this study will provide key insights into the genetic interactions that
occur in CRC and may reveal allele-specific therapeutic approaches for cancers expressing
mutant KRAS.

## Key facts

- **NIH application ID:** 9934157
- **Project number:** 7R01CA232372-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Kevin Haigis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $499,355
- **Award type:** 7
- **Project period:** 2018-06-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934157

## Citation

> US National Institutes of Health, RePORTER application 9934157, Tissue-specific genetic interactions in cancer (7R01CA232372-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934157. Licensed CC0.

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