Molecular characteristics of early-onset versus average-onset gastroesophageal adenocarcinoma.
Authors: Mahipal Amit , Teslow Emily , Yu Yingying , Yilma Binyam , Fragkogianni Stamatina , Stoppler Melissa Conrad , Jin Zhaohui 
Published: January 2025

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Background:
Incidence of early-onset gastroesophageal adenocarcinoma (eoGEA, ages <50 years) has been increasing in the United States since the 1990s, the etiology of which is still unclear, and limited data exists on molecular drivers. This study evaluates somatic and germline profiles in eoGEA compared to average-onset GEA (aoGEA, ages≥ 50 years).
Methods:
This is a retrospective, cross-sectional study utilizing data from de-identified records of GEA (esophageal, gastroesophageal junction and gastric adenocarcinomas) patients who underwent somatic NGS testing via the Tempus xT assay (595-648 gene DNA panel) from 12/2017 to 07/2024. This assay assesses somatic tumor mutations (including SNVs, Indels, CNVs, and select SVs), MSI, TMB, and incidentally detected germline SNVs and small indels in matched normal tissue. Clinical characteristics and immunotherapy markers were compared between eoGEA and aoGEA by Wilcoxon Rank Sum or Chi-squared test. Somatic and germline mutations were compared between two age groups with false discovery rate adjustments.
Results:
We compared the demographic, clinical, and molecular features of a total of 5863 patients with eoGEA (n=785, median age 43) and aoGEA (n=5078, median age 68). Over 80% of patients were diagnosed with stage IV disease. The eoGEA group had a higher proportion of females, non-white, and Hispanic or Latino patients compared to the aoGEA group (p<0.001). Prevalence of MSI-H/ dMMR, and TMB-H was lower in eoGEA vs aoGEA (p<0.001), while PD-L1 expression was similar. Prevalence of somatic
CDH1
,
CDKN2A
, and
TP53
SNVs, and
FGFR2
and
KRAS
CNAs were higher in eoGEA vs aoGEA (q<0.001). In a subset of 3286 patients with tumor/normal match testing (eoGEA=464 and aoGEA=2822), eoGEA also had a higher prevalence of germline CDH1 mutations (q<0.001).
Conclusions:
eoGEA has a unique somatic and germline mutation profile compared to aoGEA; further study evaluating the molecular landscape including epigenetic changes could shed light on underlying mechanisms responsible for the rising incidence of eoGEA.

eoGEA (n=785)
aoGEA (n=5078)
p-value/q-value*

Baseline characteristics

Median age at diagnosis (IQR)
43 (38, 47)
68 (61,74)
<0.001

Gender: male
509 (65%)
3798 (75%)
<0.001

Race (white)
280 (69%)
2347 (80%)
<0.001

Ethnicity (not hispanic or latino)
206 (60%)
1768 (86%
<0.001

Stage IV
495 (85%)
2883 (81%)
0.073

Immunologic markers

TMB ≥ 10
25 (3.2%)
519(10%)
<0.001

MSI-H
13 (1.7%)
261 (5.1%)
<0.001

dMMR
7 (2.2%)
120 (5.9%)
0.007

Somatic mutations profiles *

CDH1

126 (16%)
334 (6.6%)
<0.001

TP53

515 (66%)
3764 (74%)
<0.001

CDKN2A

101 (13%)
1011 (20%)
<0.001

KRAS

92 (12%)
931 (18%)
<0.001

NOTCH1

12 (1.5%)
228 (4.5%)
0.002

Germline mutation profiles *

eoGEA (N=464)
aoGEA (N= 2,822)

Overall prevalence
46 (9.9%)
207 (7.3%)

CDH1

10 (2.2%)
8 (0.3%)
0.001

TP53

3 (0.6%)
0 (0%)
0.039

BRCA2

2 (0.4%)
38 (1.3%)
0.6

BRIP1

4 (0.9%)
10 (0.4%)
0.6