Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 17;9(1):241.
doi: 10.1038/s41698-025-01030-4.

Multi-omic characterization of early-onset esophagogastric cancer

Lawrence W Wu  1 , Sachin Kumar Deshmukh  2 , Sharon Wu  2 , Joanne Xiu  2 , Sung Joo Jang  3 , Jimyung Park  1 , Vincent K Lam  4 , Emil Lou  5 , Sanjay Goel  6 , Rachna T Shroff  7 , Ryan H Moy  8
Affiliations

Multi-omic characterization of early-onset esophagogastric cancer

Lawrence W Wu et al. NPJ Precis Oncol. .

Abstract

Using a large real-world database with matched genomic and transcriptomic data, we characterized clinical and molecular differences between patients with early-onset esophagogastric cancer (EOEGC; <50 years), intermediate-onset esophagogastric cancer (IOEGC; 50-65 years), and average-onset esophagogastric cancer (AOEGC; >65 years). We analyzed clinicopathologic, whole transcriptome, and DNA-sequencing data from 5175 patient samples (EOEGC, n = 530; IOEGC, n = 1744; AOEGC, n = 2901) from the Caris Life Sciences database. Immune deconvolution was performed with quanTIseq and pathway enrichment with Gene Set Enrichment Analysis (GSEA). Real-world overall survival was estimated from insurance claims data. Prevalence of EOEGC was higher in patients who were Black, Asian, Hispanic/Latino, and female. Patients with EOEGC had higher proportion of CDH1 mutations; FGFR2, CCNE1, MYC copy number alterations; and ARHGAP26 fusions. Patients with EOEGC had decreased prevalence of immune-oncology markers of microsatellite instability-high, tumor mutation burden-high, and PD-L1 positivity. Immune microenvironment analysis identified significant enrichment of M2 macrophages and decreased M1 macrophages in patients with EOEGC. GSEA identified enrichment of epithelial mesenchymal transition and coagulation pathways in patients with EOEGC. This large real-world characterization of age-stratified esophagogastric cancer found that EOEGC was associated with significant racial, ethnic, and gender differences, and notable molecular differences that may have prognostic and therapeutic implications.

PubMed Disclaimer

Conflict of interest statement

Competing interests: L.W.W., S.J., J.P., and S.G. declare no competing interests. S.K.D., S.W., and J.X. are employees of Caris Life Sciences. V.K.L. has served in a consultant/advisory role for Pfizer, Genentech/Roche, Iovance Biotherapeutics, Anheart Therapeutics, Takeda, Seattle Genetics, Bristol Myers Squibb, AstraZeneca and Guardant Health, and has received research funding from GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Merck and Seattle Genetics. R.T.S. has served in a consult/advisory role for AstraZeneca, Boehringer Ingelheim Pharma, Clovis, Genentech, Incyte, Merck, QED Therapeutics, Servier, Taiho, Zymeworks Biopharm, Syros, Astellas, Natera, Hoopika Pharma, Abbvie, Duo Oncology, and has received research funding from Bayer, Bristol Myers Squibb, Exelixis Pharmaceuticals, IMV Inc, LOXO, Novocure, NUCANA, Pieris, Rafael Pharmaceuticals, Seagen. R.H.M. has served in a consult/advisory role for Puretech Health, IDEAYA Biosciences, Nimbus Therapeutics, and Amgen; and has received research funding from Nimbus Therapeutics and Repare Therapeutics.

Figures

Fig. 1
Fig. 1. Molecular alterations in EOEGC, IOEGC, and AOEGC.
A Bar graph of 21 most common mutational alterations. B Bar graph of 11 most common copy number alterations. C Bar graph of 3 most common fusions. *p < 0.05; **p < 0.01; ***p < 0.001 when compared to EOEGC by chi-square or Fisher’s exact tests.
Fig. 2
Fig. 2. Immuno-oncology biomarkers in EOEGC, IOEGC, and AOEGC.
A Bar graph for TMB-High status (≥10 mutations/MB). B Bar graph for dMMR/MSI-H status. C Bar graph for PD-L1 positive status as determined by immunohistochemistry from the 22c3 assay. *p < 0.05; **p < 0.01; *** p < 0.001 when compared to EOEGC by chi-square or Fisher’s exact tests.
Fig. 3
Fig. 3. Immune cell infiltrate and immune gene expression in EOEGC, IOEGC, and AOEGC.
A Computationally inferred intratumoral immune population. The heatmap indicates fold change of IOEGC relative to EOEGC in median immune fraction according to quanTIseq. B The heatmap indicates fold change of AOEGC relative to EOEGC in median immune fraction according to quanTIseq. Tumor microenvironment cell fractions were analyzed among cohorts using nonparametric Kruskal-Wallis testing. The Benjamini-Hochberg method was utilized to adjust p-values for multiple comparisons (*q < 0.05; **q < 0.01; ***q < 0.001). C For cell types with median values of “0”(Ex: monocytes and CD4+ T cells), the percentage of tumors with nonzero immune infiltrates were compared. D Fold change gene expression levels in transcripts per million (TPM) of immune checkpoint genes IOEGC relative to EOEGC. E Fold change gene expression levels in TPM of immune checkpoint genes AOEGC relative to EOEGC. Mann-Whitney U test used to determine statistically significant differences in immune gene expression. The Benjamini-Hochberg method was utilized to adjust p-values for multiple comparisons (*q < 0.05; **q < 0.01; ***q < 0.001).
Fig. 4
Fig. 4. Gene set enrichment analysis (GSEA) in EOEGC, IOEGC, and AOEGC.
A GSEA differences in pathways based on normalized enrichment scores (NES) in EOEGC versus IOEGC. B GSEA differences in pathways based on NES in EOEGC versus AOEGC. Positive NES would imply higher values in EOEGC. All pathways with false discovery rate (FDR) <0.25.
Fig. 5
Fig. 5. Real world overall survival (rwOS) for patients with EOEGC, IOEGC, and AOEGC stratified by treatment.
A Kaplan-Meier curves of rwOS of patients with EOEGC, IOEGC, AOEGC after treatment with chemotherapy (Defined as Carboplatin, Cisplatin, Docetaxel, Fluorouracil, Oxaliplatin, Paclitaxel, FOLFIRI, FOLFOX, FOLFIRINOX). B rwOS stratified by CDH1-mutation status after treatment with chemotherapy. C rwOS after treatment with immune checkpoint inhibitor with pembrolizumab or nivolumab. Log-rank test was performed with significance determined as p < 0.05.
See this image and copyright information in PMC

References

    1. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin.68, 394–424 (2018). - PubMed
    1. Ferlay, J. et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J. Cancer144, 1941–1953 (2019). - PubMed
    1. Islami, F., DeSantis, C. E. & Jemal, A. Incidence Trends of Esophageal and Gastric Cancer Subtypes by Race, Ethnicity, and Age in the United States, 1997-2014. Clin. Gastroenterol. Hepatol.17, 429–439 (2019). - PubMed
    1. Bergquist, J. R. et al. Early-onset gastric cancer is a distinct disease with worrisome trends and oncogenic features. Surgery166, 547–555 (2019). - PubMed
    1. Codipilly, D. C. et al. Epidemiology and Outcomes of Young-Onset Esophageal Adenocarcinoma: An Analysis from a Population-Based Database. Cancer Epidemiol. Biomark. Prev.30, 142–149 (2021). - PMC - PubMed

LinkOut - more resources