Multi-omic analysis of Esophageal Adenocarcinoma uncovers candidate therapeutic targets and cancer-selective post-transcriptional regulation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209805%3A_____%2F24%3A00079750" target="_blank" >RIV/00209805:_____/24:00079750 - isvavai.cz</a>

Result on the web

<a href="https://pubmed.ncbi.nlm.nih.gov/38604503/" target="_blank" >https://pubmed.ncbi.nlm.nih.gov/38604503/</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.mcpro.2024.100764" target="_blank" >10.1016/j.mcpro.2024.100764</a>

Result language

angličtina

Original language name

Multi-omic analysis of Esophageal Adenocarcinoma uncovers candidate therapeutic targets and cancer-selective post-transcriptional regulation

Original language description

BACKGROUND: Efforts to address the poor prognosis associated with esophageal adenocarcinoma (EAC) have been hampered by a lack of biomarkers to identify early disease and therapeutic targets. Despite extensive efforts to understand the somatic mutations associated with EAC over the past decade, a gap remains in understanding how the atlas of genomic aberrations in this cancer impacts the proteome and which somatic variants are of importance for the disease phenotype. METHODS: We performed a quantitative proteomic analysis of 23 EACs and matched adjacent normal esophageal and gastric tissues. We explored the correlation of transcript and protein abundance using tissue-matched RNA-seq and proteomic data from 7 patients and further integrated these data with a cohort of EAC RNA-seq data (n=264 patients), EAC whole-genome sequencing (n=454 patients) and external published datasets. CENTRAL FINDINGS: We quantified protein expression from 5879 genes in EAC and patient-matched normal tissues. Several biomarker candidates with EAC-selective expression were identified including the transmembrane protein GPA33. We further verified the EAC-enriched expression of GPA33 in an external cohort of 115 patients and confirm this as an attractive diagnostic and therapeutic target. To further extend the insights gained from our proteomic data, an integrated analysis of protein and RNA expression in EAC and normal tissues revealed several genes with poorly correlated Protein and RNA abundance, suggesting post-transcriptional regulation of protein expression. These outlier genes including SLC25A30, TAOK2, and AGMAT, only rarely demonstrated somatic mutation suggesting post-transcriptional drivers for this EAC-specific phenotype. AGMAT was demonstrated to be over-expressed at the protein level in EAC compared to adjacent normal tissues with an EAC-selective, post-transcriptional mechanism of regulation of protein abundance proposed. CONCLUSIONS: By quantitative proteomic analysis we have identified GPA33 as an EAC-selective biomarker. Integrated analysis of proteome, transcriptome, and genome in EAC has revealed several genes with tumor-selective, post-transcriptional regulation of protein expression which may be an exploitable vulnerability.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30204 - Oncology

Project

<a href="/en/project/EF16_019%2F0000868" target="_blank" >EF16_019/0000868: Molecular, cellular and clinical approach to healthy ageing</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Molecular &amp; cellular proteomics : MCP

ISSN

1535-9476

e-ISSN

1535-9484

Volume of the periodical

23

Issue of the periodical within the volume

6

Country of publishing house

US - UNITED STATES

Number of pages

16

Pages from-to

100764

UT code for WoS article

001347663100001

EID of the result in the Scopus database

2-s2.0-85197347180