Purity Independent Subtyping of Tumors (PurIST), A Clinically Robust, Single-sample Classifier for Tumor Subtyping in Pancreatic Cancer

Abstract

Purpose: Molecular subtyping for pancreatic cancer has made substantial progress in recent years, facilitating the optimization of existing therapeutic approaches to improve clinical outcomes in pancreatic cancer. With advances in treatment combinations and choices, it is becoming increasingly important to determine ways to place patients on the best therapies upfront. While various molecular subtyping systems for pancreatic cancer have been proposed, consensus regarding proposed subtypes, as well as their relative clinical utility, remains largely unknown and presents a natural barrier to wider clinical adoption. Methods:We assess three major subtype classification schemas in the context of results from two clinical trials and by meta-analysis of publicly available expression data to assess statistical criteria of subtype robustness and overall clinical relevance. We then developed a Single Sample Classifier (SSC) using penalized logistic regression based on the most robust and replicable schema.

Image-Based Molecular Phenotyping of Pancreatic Ductal Adenocarcinoma

“…Furthermore, any definition of PDAC subtypes may suffer from label noise, and it cannot be conclusively resolved at this point, how robustly the applied histopathological methodology can represent the transcriptome-based molecular phenotype [22]. Nevertheless, the highly significant separation of survival in the unclassifiable tumor subgroup observed in our study seems to support the binary classification of PDAC subtypes as recently proposed [27].…”

Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

“…These include a "basal-like" (or squamous) subtype, which is poorly differentiated and carries a worse prognosis when compared with the better-differentiated "classical" (or progenitor) subtype (4,7,10). Basal-like and classical subtypes have been shown to share features of the squamous and progenitor subtypes, respectively, as defined by an independent PDAC classification system (5,11,12), which also can predict response to chemotherapy (6,(13)(14)(15). In addition, the basal-like subtype is associated with the activation of genes involved in the epithelial-mesenchymal transition (EMT), activation of the transcription factors MYC and TP63, and downregulation of endodermal identity markers, such as HNF4A and GATA6, whose expression are therefore hallmarks of the classical subtype (4,6,7).…”

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

“…PDX were ranked into five different histological classes by two blinded expert pathologists ranging from the less differentiated PDX (class I), which is associated with the most aggressive phenotype, to the most differentiated PDX (class V; Figure S1). The here described five histological classes of PDX strongly correlates with the expression of genes defining the already described molecular subtypes [6][7][8][9] as higher expression of genes linked to the classical PDAC subtype is correlated with increased differentiation of PDX samples, combined with lower expression of genes linked to basal-like subtype (Figure 1a and Figure S1). Interestingly, the variation in the expression of the classical genes towards the basal-like genes vary gradually from the more differentiate to the less differentiate histological classes respectively.…”

“…Several studies using only resectable tumors show molecular diversity of the epithelial compartment of PDAC is associated with tumor aggressiveness and patient prognosis [7,8,14]. Our next goal was to determine if the PAMG could be predictive in all PDAC tumors.…”

“…It was previously suggested that molecular subtypes of PDAC were associated with responses to chemotherapy, in particular FOLFIRINOX [8,15,16]. Therefore, to evaluate the predictive value of the PAGM to chemotherapy response, it was applied to metastatic patients in the COMPASS trials for which transcriptomic profiles and tumor responses to mFOLFIRINOX were available [16].…”