# A cancer-derived truncating mutation in disease penetrance and progression of MSI CRC

> **NIH NIH R01** · WISTAR INSTITUTE · 2022 · $565,848

## Abstract

Project Summary
Colorectal cancer (CRC) ranks as the 2nd most common cause of cancer mortality. Nearly all
patients suffering from Lynch Syndrome as well as 15-20% of patients with sporadic early CRC
have microsatellite instability (MSI) due to DNA mismatch repair (MMR) deficiency. Notably,
defective MMR by itself is not sufficient to drive cell transformation and tumorigenesis, but
microsatellite mutations in a limited number of target genes might be positively selected during
tumor development, underlying MSI-associated pathogenesis. Unfortunately, relatively little is
known about the molecular underpinnings of MSI target genes and their mechanism of action in
MSI-associated disease penetrance. This project will fill this gap, capitalizing on our recent
discovery of a strong correlation between the MSI phenotype and recurrent frameshift (FS)
mutation in the autophagy tumor suppressor UVRAG. The protein product of this FS mutation
functions as an oncogene and a bona fide trigger of centrosome amplification (CA) in CRC. We
now bring within this proposal a collaboration of leaders in CRC genetics and molecular biology
along with clinicians and pathologists to understand the molecular mechanism by which CA
augments the expressivity of MMR mutations, contributing to human colonic carcinogenesis. To
achieve this goal, we propose three Specific Aims, including (1) identifying the molecular
mechanism of CA in MSI CRC associated with UVRAGFS expression; (2) examining the impact
of CA on the differentiation and metastatic capacity of MSI patient-derived colonic organoids;
and (3) investigating the in vivo role of MSI-derived UVRAGFS in disease penetrance and cancer
progression using targeted mutant mouse models. These aims will be addressed using
multidisciplinary innovative approaches that integrate state-of-the-art genetic, biochemistry, live-
cell imaging, and physiological assays in cells and in mice with targeted mutations in genes
related to MMR deficiency and centrosome deregulation. We have access to the right cohort of
patients and our use of patient-derived colonic organoids will maximize the relevance of our
findings for eventual translation to cancer patients in the clinic. Together, we anticipate that our
studies will delineate a novel mechanism underlying MSI-associated disease penetrance and
provide compelling in vivo validation of CA as a novel prognostic and predictive biomarker and a
therapeutic target for personalized treatment of MSI CRC including Lynch Syndrome.

## Key facts

- **NIH application ID:** 10320079
- **Project number:** 5R01CA238457-04
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Chengyu Liang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $565,848
- **Award type:** 5
- **Project period:** 2020-08-06 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320079

## Citation

> US National Institutes of Health, RePORTER application 10320079, A cancer-derived truncating mutation in disease penetrance and progression of MSI CRC (5R01CA238457-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10320079. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*