# Pathogenic Germline Mutations in Barrett's Esophagus

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $622,003

## Abstract

PROJECT SUMMARY: Esophageal adenocarcinoma (EAC) remain among the most lethal cancers, with a 5-
year survival rate of ~20%. Present in 1-6% of the general population, Barrett’s Esophagus (BE) has been
identified as the definitive precursor lesion, but confers a risk of progression at an astoundingly low rate of
0.12% per year. Despite identification of multiple clinical risk factors for progression, such factors alone are not
sufficient to explain why so few individuals subsequently develop high-grade dysplasia and adenocarcinoma.
Extensive somatic genomic characterization of non-dysplastic Barrett’s Esophagus and EAC have
demonstrated that early acquisition of TP53 mutations (prevalence 70-83%) and subsequent genome doubling,
aneuploidy, and/or chromothriptic events as genomic hallmarks of BE progression. However, these somatic
alterations have not yielded insight to why so few individuals with BE progress to dysplasia, or account for the
25-30% of tumors with wildtype TP53. Our robust preliminary data from 742 BE progressors reveal that
individuals who progress are enriched with pathogenic germline mutations in cancer-predisposing genes
associated with multicancer susceptibility, and that these inheritable mutations can shape the somatic
mutanome in Barrett’s esophagus. Moreover, these germline mutations are enriched in TP53 wildtype tumors.
In Aim #1, we seek to provide more precise risk estimates of germline alterations occurring in two prevalent
genes associated with TP53-wildtype tumor development, ATM and BRCA2. In Aim #2, we assess if
introduction of heterozygosity of ATM and BRCA2, the most commonly mutated genes that demonstrate
mutual exclusivity with TP53, into nondysplastic BE organoids accelerate accumulation of copy number
alterations. In Aim #3, we perform single-cell copy number analysis of BE from BRCA2 and ATM mutation
carriers to see if such individuals demonstrate increased subchromosomal aneuploidy compared to matched
controls. Understanding how enriched germline driver mutations, particularly those that remain heterozygous in
Barrett’s esophagus and retain wildtype TP53 acquire high-risk genomic features is critical for comprehensive
risk assessment, biomarker design, and chemoprevention efforts.

## Key facts

- **NIH application ID:** 10980893
- **Project number:** 1R01DK137971-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Manish Gala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $622,003
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980893

## Citation

> US National Institutes of Health, RePORTER application 10980893, Pathogenic Germline Mutations in Barrett's Esophagus (1R01DK137971-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10980893. Licensed CC0.

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