27P - Proteomic profiling reveals organ-specific differences in metastases and identifies potential biomarkers for recurrence risk in localized colon cancer

Background

Up to 36% of patients with localized colon cancer (LCC) do not clear circulating tumor DNA after adjuvant chemotherapy (ACT) and experience a recurrence. Identifying recurrence risk signatures and selecting patients for more personalized adjuvant therapies relies on comprehending cellular resistance mechanisms and the host tissue microenvironment. Our project's goal is to analyze the proteomic profile of primary tumors (PTs) with a high risk of relapse and organ-specific metastatic lesions to enhance personalized therapeutic strategies.

Methods

At the Hospital Clínico Universitario of Valencia, Spain, we conducted a proteomic analysis using SWATH mass spectrometry on 80 tissue samples from patients with LCC. Of these, 28 PTs samples from non-relapsed patients and 52 samples of 25 relapsed patients with PTs and paired metastases (METs) were analyzed. Differential expression (DE) analysis was performed using the R package Limma and functional enrichment analysis was done by GO, with a significance threshold set at FDR<0.05.

Results

SWATH analysis revealed 308 DE proteins between PTs and METs, with 12 proteins being overexpressed in METs and 296 in PTs. Interestingly, distinctive proteomic profiles were observed among different metastatic sites, particularly in liver lesions. GO analysis of the overexpressed MET proteins indicated enrichment in nucleic acid binding and structural molecule activity. The proteins overexpressed in PTs showed enrichment in catalytic and oxidoreductase activity, as well as molecule binding, among the top 10 pathways. Additionally, when comparing PTs from relapsed and non-relapsed patients, 206 DE proteins were identified. A Cox survival analysis revealing changes in protein levels associated with worse disease-free survival, including IWS1 and DPYSL4.

Conclusions

We discovered a specific proteomic signature for metastases, particularly in liver lesions, highlighting the significance of organ-specificity in metastatic development. Moreover, we identified novel proteins as potential biomarkers for poor prognosis in primary tissue, improving patient risk stratification.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III.

Disclosure

V. Gambardella: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Institutional, Other, Research: Research Funding: Bayer, Boehringer Ingelheim; Roche; Financial Interests, Institutional, Other, Institutional: Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. A. Cervantes: Financial Interests, Institutional, Advisory Board: Merck-Serono, Amgen, Roche, Transgene, AnHeart Therapeutics, AbbVie, GSK; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor in Chief: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, Beigene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda, Affimed, Roche, Seamless, Gilead, Janssen, F. STAR Therapeutics, Ribon Therapeutics; Non-Financial Interests, Personal, Other, Scientific Director: INCLIVA Biomedical Research Institute. N. Tarazona Llavero: Financial Interests, Personal, Advisory Board: Merck, Guardant Health; Financial Interests, Personal, Invited Speaker: Merck, Pfizer, Servier, Amgen; Financial Interests, Institutional, Funding: Natera Inc.; Non-Financial Interests, Personal, Member: SEOM Committee. All other authors have declared no conflicts of interest.