# Center for Gastric Pre-Cancer Atlas of Multidimensional Evolution in 3D (GAME3D)

> **NIH NIH U01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $1,069,873

## Abstract

PROJECT SUMMARY
This application aims to address the urgent need for precision in intercepting hereditary diffuse gastric cancer
(HDGC) associated with pathogenic germline CDH1 mutations, elevating lifetime cancer risk up to 80% for
developing advanced diffuse gastric cancer (AGC), particularly at a young age. HDGC patients pose unique
challenges in cancer interception and risk reduction due to the aggressive nature of AGC, which is associated
with a poor prognosis. Consequently, those with pathogenic CDH1 mutation are advised to undergo prophylactic
total gastrectomies (PTG), However, the incidence of AGC in CDH1 carries varies significantly, with only 25-45%
of mutation carries develop AGC while many patients remain negative during surveillance (normal-appearing
mucosa, N) or stable at the T1a stage (intramucosal stage which is considered as the “precancerous” lesion of
AGC in the context of HDGC) without progression to AGC in years or even lifetime. These facts indicate that
PTG, a major operation associated with chronic physical and psychosocial disabilities, may not be necessary for
all CDH1 mutation carries, however, previous attempts to stratify risk based on specific variants or family cancer
history have not been successful and tools to identify patients at high risk of AGC development, potentially
requiring PTG, are currently lacking. This is largely due to our limited understanding of the earliest events that
drive T1a lesion development and progression. To fill this void, we assembled the Center for Gastric Pre-Cancer
Atlas of Multidimensional Evolution in 3D (GAME3D) that is composed of scientists who work closely together
bridging multiple disciplines, have longstanding expertise in pathobiology of HDGC, and who developed
innovative workflows for multimodal characterization and modeling of the N-T1a-AGC pathologic continuum in
CDH1 germline mutation carriers. The overall objective of our GAME3D Research Center is to develop a
multimodal, single-cell, dynamic, and 3D spatial atlas of normal-appearing mucosa, T1a lesion, and AGC
through longitudinal samples from CDH1 mutation carriers that will inform of transition of at-risk mucosa
to T1a lesions and then to AGC. Aim 1 will build a multimodal, dynamic, 2D spatial atlas that maps the transition
of T1a lesion from at-risk mucosa and its subsequent evolution to AGC. Aim 2 will employ revolutionary technical
and computational approaches and build a spatiotemporal three-dimensional (3D) atlas at single-cell resolution
that captures the N-T1a-AGC pathologic continuum. Aim 3 will leverage complete use cases and 2D and 3D
atlases to build computational models of tumor initiation in normal-appearing gastric mucosa, pathogenesis and
progression of T1a lesions, and, ultimately, the N-T1a-AGC pathologic continuum. Our atlas is of high-value to
the current HTAN repertoire as it will provide an exceptional view into the single-cell spatial landscape of the N-
T1a-AGC pathologic continuum, thereby ...

## Key facts

- **NIH application ID:** 10994921
- **Project number:** 1U01CA294518-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Tae Hyun Hwang
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,069,873
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994921

## Citation

> US National Institutes of Health, RePORTER application 10994921, Center for Gastric Pre-Cancer Atlas of Multidimensional Evolution in 3D (GAME3D) (1U01CA294518-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10994921. Licensed CC0.

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