# Early TP53 Mutations and Genomic Doubling as a Novel Path for Barrett's Esophagus Progression

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $81,567

## Abstract

PROJECT SUMMARY
 Intestinalization of the esophagus, termed Barrett’s esophagus (BE), is thought to develop in response
to chronic acid and bile reflux and carries great clinical significance because it is the precursor to esophageal
adenocarcinoma (EAC). The incidence of BE is quite high, estimated to be found in at least 1:100 people. While
relatively few with BE progress to cancer there is great importance to being able to detect those at risk of
progression. Efforts to screen for high risk disease in those with BE have, to date, not been very successful.
Therefore, there is profound need to define the process by which BE progresses into EAC, to develop biomarkers
to diagnose early progression and assess progression risk in BE tissues. The objective of this mentored research
career development proposal is to investigate the molecular underpinnings of Barrett’s esophagus progression
with the long term goal to develop better screening strategies and biomarkers to identify those at risk of
progression at an early curable stage. To determine when and where key alterations in BE progression occur,
laser capture microdissection and sequencing of histologically defined areas of BE, dysplasia, and EAC will be
performed. These alterations will then be modeled in both an in vitro and in vivo setting to determine their
functional significance. The role of acid and bile exposure to BE progression and how these exposures interact
with genetic alterations will be investigated using the same model systems. These research studies encompass
a wide array of disciplines including gastrointestinal pathology, Barrett’s biology, massively parallel
sequencing/genetics, and in vitro and in vivo (mouse) model development, which together will help define the
process of BE progression as well as provide a well rounded career development pathway to becoming an
independent investigator through the following specific aims:
Aim 1: To define the timing of TP53 mutations and genomic doubling in Barrett’s esophagus progression
relative to onset of dysplasia and acquisition of other genomic alterations.
Aim 2: To test the hypothesis in in vitro and in vivo models of Barrett’s esophagus that TP53 mutations
facilitate acquisition of genomic doubling, aneuploidy, and oncogene amplification leading to neoplastic
transformation.
Aim 3: To determine the effect of acidic pH and bile salt exposure on Barrett's epithelial progression.
 This career development award candidate is a M.D./Ph.D. with board certification in anatomic and
molecular genetic pathology. The research proposed in this grant application will be conducted under the co-
mentorship of Dr. Thea Tlsty at the University of California San Francisco. The candidate is committed to a
career as a physician scientist and seeks further training to facilitate his transition to become a NIH-funded
independent investigator in the field of gastrointestinal disease.

## Key facts

- **NIH application ID:** 10380456
- **Project number:** 3K08DK109209-05S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Matthew D Stachler
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $81,567
- **Award type:** 3
- **Project period:** 2016-04-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380456

## Citation

> US National Institutes of Health, RePORTER application 10380456, Early TP53 Mutations and Genomic Doubling as a Novel Path for Barrett's Esophagus Progression (3K08DK109209-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10380456. Licensed CC0.

---

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