Understanding the biology of disparity-associated genomically stable gastric tumors

PROJECT SUMMARY
Gastric cancer (GC) has a high mortality rate in Latinos. This is likely the result of multi-level social determinants
of health and population-specific factors. Our recent cancer registry-based study showed that Latinos have high
rates of poor prognosis diffuse GCs. Compared to intestinal-type tumors, Latinos with diffuse tumors had ~50%
lower 5-year survival. In addition to the histological classification, TCGA described four GC molecular subtypes,
including the genomically stable (GS) subtype, characterized by diffuse histology, low mutation and copy number
alteration rates and a high frequency of “undruggable” CDH1 and RHOA mutations. GS tumors are
chemotherapy-resistant, immunologically “cold,” and have the worst prognosis. Interestingly, we recently showed
that ~50% of all Latino patients have GS tumors, a fraction that is >3-fold higher than in Asians and Whites.
Hence, our studies suggest that Latinos are enriched with poor prognosis GC histological and molecular
subtypes, partly explaining GC disparities. Given the high GS prevalence in Latinos, we obtained paired tumor-
normal reduced representation bisulfite sequencing (RRBS) data from 15 Latino patients and re-analyzed TCGA
methylation data to carry a preliminary GS epigenome analysis. We found that GS tumors, compared to other
subtypes, are enriched with differentially methylated genes (DMGs) in key pathways such as WNT, TGF-beta
and PI3K/AKT signaling, which may explain their aggressiveness and chemoresistance. Our analyses also
highlighted key limitations of existing publicly available GS epigenome data. For example, TCGA lacked Latino
samples and profiled primarily tumor-only samples using sub-optimal methods as we found that RRBS identified
many methylated regions that were missing in TGCA methylation arrays and which appeared to be GS-tumor,
and possibly Latino-specific. Our preliminary studies therefore highlighted several research gaps that will be
addressed in the present application. The objectives of the present application are to advance our
understanding of GS tumor biology using epigenomic and functional genomic approaches. To this end, we will
leverage our expertise in cancer biology, health disparities, patient-derived modeling, preclinical studies, and
genome engineering. Our hypothesis is that Latino GS tumorigenesis follows unique biological pathways, some
which may be amenable to therapeutic development. In Aim 1, we will characterize the epigenome of 100 Latino
GS tumors using RRBS. Aim 2 will investigate GS tumorigenesis using ethnic-appropriate Latino gastric
organoids and isogenic modeling for CDH1 and RHOA. In Aim 3, we will perform a loss of function screen that
will be used to identify synthetically lethal associations in CDH1- and RHOA-mutant GS cell lines, some of that
maybe amenable to molecularly guided therapies. Our study will significantly advance our understanding of GS
tumors' biology and therapeutic vulnerabilities. As GS tumors are likely drivers of higher mortality rates in Latinos,
our study will also significantly advance cancer health equity in the country.

Grant Number: 5R56CA280636-02
NIH Institute/Center: NIH
Principal Investigator: Luis Carvajal Carmona