Cited by 591Pancreatic and Hepatic Oncology ResearchCancer Genomics and DiagnosticsBreast Cancer Treatment Studies

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Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features

Puleo, Francesco, Nicolle, Rémy, Blum, Yuna, Cros, Jérôme, Marisa, Laetitia, Demetter, Pieter, Quertinmont, Eric, Svrcek, Magali, Elarouci, Nabila, Iovanna, Juan, Franchimont, Denis, Verset, Laurine, Galdon, Maria Gomez, Devière, Jacques, de Reyniès, Aurélien, Laurent-Puig, Pierre, Van Laethem, Jean-Luc, Bachet, Jean-Baptiste, Maréchal, Raphaël·2018·Gastroenterology

DOI 10.1053/j.gastro.2018.08.033

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Abstract

Background & aims Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation.Methods We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts.Results We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue).Conclusions We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.

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Authors: Puleo, F., Nicolle, R., Blum, Y., Cros, J., Marisa, L., Demetter, P., Quertinmont, E., Svrcek, M., Elarouci, N., Iovanna, J., Franchimont, D., Verset, L., Galdon, M. G., Devière, J., de Reyniès, A., Laurent-Puig, P., Van Laethem, J.-L., Bachet, J.-B., & Maréchal, R.
Affiliations: Université Libre de Bruxelles (BE)
La Ligue Contre le Cancer (FR)
Erasmus Hospital (BE)
Hôpital Saint-Antoine (FR)
Centre National de la Recherche Scientifique (FR)
Pitié-Salpêtrière Hospital (FR)
Corresponding author: Puleo, Francesco
ORCID: Puleo, Francesco
Nicolle, Rémy
Blum, Yuna
Marisa, Laetitia
Demetter, Pieter
Quertinmont, Eric
Svrcek, Magali
Elarouci, Nabila
Iovanna, Juan
Franchimont, Denis
Verset, Laurine
Galdon, Maria Gomez
Laurent-Puig, Pierre
Bachet, Jean-Baptiste
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2018-12
Volume: 155
Issue: 6
Pages: 1999-2013.e3
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2018.08.033
OpenAlex: W2889433609
Cited by: 563
References: 34
Citations by year: 2026: 53 · 2025: 63 · 2024: 66 · 2023: 87 · 2022: 81 · 2021: 109 · 2020: 72 · 2019: 28 · 2018: 4
FWCI: 20.20
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Gastroenterology (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords: pancreatic ductal adenocarcinoma, tumor subtypes, tumor microenvironment, gene expression profiling, formalin-fixed paraffin-embedded tissue, desmoplasia, basal-like subtype, classical subtype, overall survival, disease-free survival, independent component analysis, consensus clustering
MeSH terms: Progression-Free Survival, Adenocarcinoma, Adult, Aged, Aged, 80 and over, DNA, Neoplasm, Female, Humans, Male, Middle Aged, Pancreas, Prospective Studies, Regression Analysis, RNA, Neoplasm, Gene Expression, Proportional Hazards Models, Sequence Analysis, DNA, Disease-Free Survival, Carcinoma, Pancreatic Ductal, Pancreas, Exocrine, Tumor Microenvironment, Transcriptome, Acinar Cells

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Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features

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