Abstract
BACKGROUND: The purpose of the study was to conduct a
comprehensive genomic characterization of gene alterations,
microsatellite instability (MSI), and tumor mutational burden
(TMB) in submucosal-penetrating (Pen) early gastric cancers
(EGCs) with varying prognoses. METHODS: Samples from EGC
patients undergoing surgery and with 10-year follow-up data
available were collected. Tissue genomic alterations were
characterized using Trusight Oncology panel (TSO500). Pathway
instability (PI) scores for a selection of 218 GC-related
pathways were calculated both for the present case series and
EGCs from the TCGA cohort. RESULTS: Higher age and tumor
location in the upper-middle tract are significantly associated
with an increased hazard of relapse or death from any cause (p =
0.006 and p = 0.032). Even if not reaching a statistical
significance, Pen A tumors more frequently present higher TMB
values, higher frequency of MSI-subtypes and an overall increase
in PI scores, along with an enrichment in immune pathways.
ARID1A gene was observed to be significantly more frequently
mutated in Pen A tumors (p = 0.006), as well as in patients with
high TMB (p = 0.027). Tumors harboring LRP1B alterations seem to
have a higher hazard of relapse or death from any cause (p =
0.089), being mutated mainly in relapsed patients (p = 0.093).
CONCLUSIONS: We found that the most aggressive subtype Pen A is
characterized by a higher frequency of ARID1A mutations and a
higher genetic instability, while LRP1B alterations seem to be
related to a lower disease-free survival. Further investigations
are needed to provide a rationale for the use of these markers
to stratify prognosis in EGC patients.
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