Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome

Abstract

IntroductionTranscriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC.DesignWe first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes.ResultsWe identified four morphological patterns that segregated into two components (‘gland forming’ and ‘non-gland forming’) based on the presence/absence of well-formed glands. A morphological cut-off (≥40% ‘non-gland forming’) was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as ‘classical’ using RNA-Seq.ConclusionOur study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

Image-Based Molecular Phenotyping of Pancreatic Ductal Adenocarcinoma

“…The potential benefit of a radiomic workflow consequently lies in volumetric whole-tumor assessment, providing an opportunity to establish a clinically relevant phenotyping system and to better inform precision therapy regimens, and this concept of correlating quantitative morphometric evaluation with molecular phenotypes has been recently demonstrated for PDAC [23].…”

Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer

“…Additional file 1: Figure S1. The TCGA cohort patients formed clusters of: (1) benign (n=36), (2) early development and differentiation (n=86), (3) transition (n=36), and (4) QM-PDA (n=20) based on differential gene expression patterns.…”

“…Understanding the biological behaviors and molecular alterations that occur during the progression from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDA) is essential for the identification of clinically relevant biomarkers for early detection and diagnosis, the development of preventive and therapeutic strategies, and the control of PDA progression [1]. Collisson et al [2] evaluated the gene expression profiles of microdissected PDA samples and categorized PDA initially into three subtypes, "classical" [3], "quasi-mesenchymal" (QM-PDA), and exocrine-like [4], which all correlate with clinical outcome [2,5,6] (reviewed in [7]). An increasing number of studies then compared the differences in the stroma, immune cell infiltration, and metabolic alterations to further elaborate on the classical, the basal-like [8][9][10][11], and the squamous cells that closely resemble the QM-PDA subtype [10,[12][13][14][15], which is associated with the worst survival outcome.…”

Mitophagy in Pancreatic Cancer

“…However, autophagy plays a dual role in various cancer (including PDAC), depending on many factors, such as tumor stage, tumor microenvironment, gene mutation status involving oncogenes and tumor suppressor genes, and metabolic reprogramming (49)(50)(51)(52)(53)(54). PDAC is a heterogeneous disease and can be morphologically classified into four types: conventional, tubulopapillary, squamous, and "composite", which exhibit different molecular and genetic characteristics (55). Generally, autophagy inhibits the growth of PDAC in the early stage by limiting DNA damage or inflammation, and upregulated autophagy in the later stage can promote PDAC survival by limiting cell death or antitumor immunity (56)(57)(58)(59)(60).…”