Gene Expression Profiling of Morphologic Subtypes of Pancreatic Ductal Adenocarcinoma Using Surgical and EUS-FNB Specimens.

Background/objectives: Various classifications of pancreatic ductal adenocarcinoma (PDAC) based on RNA profiling resulted in two main subtypes. Kalimuthu and coworkers proposed a morphology-based classification that concurred with these subtypes. Immune therapy approaches in PDAC were so far disappointing. Morphologic PDAC subtypes may differ regarding key immune-oncology pathways. We aimed to examine the reproducibility and prognostic value of Kalimuthu's morphologic classification, and to evaluate differences between subtypes regarding gene expression related to tumor biology and immune-oncology. Methods: PDAC specimens from 196 patients were included, 108 consecutive chemotherapy-naive surgical specimens and 88 endoscopic ultrasound-guided fine needle biopsies (EUS-FNBs). The specimens were evaluated as per Kalimuthu by two pancreatic pathologists, resulting in Group A and Group B tumors. Digital mRNA expression profiling was performed, on the surgical specimens using the NanoString IO360 panel of 770 key tumor biology related and 30 custom-genes, and on the EUS-FNBs using a targeted panel of 123 genes. Results: Morphologic subtyping reached substantial interobserver agreement between the two pathologists. In the surgical and EUS-FNB cohorts, 44.4% and 38.6% were Group A tumors, which were associated with improved survival. Group A showed higher expression of immune-related genes and cytokine/chemokine/interleukin signaling and Group B of genes related to cancer cell proliferation and cell cycle regulation. Hierarchical clustering based on significant differences in gene expression levels between Groups A and B revealed clusters with prognostic value. Conclusions: Morphologic subtyping according to Kalimuthu is reproducible and holds prognostic value, in surgical as well as EUS-FNB specimens. As upregulation of immune-related genes was found in Group A, future studies should evaluate the potential of immune therapy approaches with special emphasis on this subtype of PDAC. (C) 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.