# Deciphering How Esco2 Loss Acts as a Penetrance Modifier

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $339,281

## Abstract

Abstract
Li Fraumeni patients, which harbor heterozygous p53 germ line mutation, are highly predisposed to cancers.
The penetrance of these individuals can vary greatly; some individuals have tumor onset prior to age 1, while
some individual that do not present with cancer by age 74. P53 is the most widely mutated gene in sporadic
cancers, therefore understanding the mechanisms that impact tumor penetrance will have great benefit to pre-
dicting individual cancer risk. We have made the unique observation that haploinsufficient Esco2 loss, in both
zebrafish and mouse, accelerated tumor formation in a p53 heterozygous animals, but not p53 wild type or
homozygous null animal. In addition we observe a high proportion of cells in Esco2 heterozygous null animals
to have reduced sister chromatid cohesion (SCC). These observations establish our hypothesis that reduced
SCC results in increased rates of loss of heterozygosity, which accelerates the timing of tumor initiation and
enhanced tumor penetrance. Within this proposal we will address this hypothesis and decipher the mechanism
of how Esco2 loss acts as a penetrance modifier. Aim 1, determine if there are accelerated LOH rates, and the
type/s of genomic instability that drive accelerated tumorigenesis, in tumors from animals with reduced cohe-
sion; Aim 2, determine if the extent of tumor enhancement is dependent on the extent of cohesion dysfunction;
Aim 3, determine if biochemically if reduced acetylation by the cohesion establishment factor, ESCO2 lends to
reduced cohesion and tumor enhancement. The expected overall impact of the proposed work is that it will
fundamentally advance our mechanistic understanding of a how SCC dysfunction impacts tumorigenesis. This
will serve as the foundation for future therapeutic intervention and predictive biomarkers of cancer risk.

## Key facts

- **NIH application ID:** 10128403
- **Project number:** 5R01CA216108-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** John M Parant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $339,281
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128403

## Citation

> US National Institutes of Health, RePORTER application 10128403, Deciphering How Esco2 Loss Acts as a Penetrance Modifier (5R01CA216108-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128403. Licensed CC0.

---

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