The Prognostic, Predictive and Clinicopathological Implications of KRT81/HNF1A- and GATA6-Based Transcriptional Subtyping in Pancreatic Cancer

Background: Transcriptional subtypes of pancreatic ductal adenocarcinoma (PDAC) based on the expression of hallmark genes may have prognostic implications and potential predictive functions. The two most employed subtyping markers assess the combined expression of KRT81 and HNF1A or of GATA6 alone, which can be detected by immunohistochemistry (IHC). This study aimed to determine the prognostic or predictive impact of both subtyping marker panels in two large cohorts of advanced and resected pancreatic ductal adenocarcinoma (PDAC) patients. Methods: Transcriptional subtypes were determined by combining the expression of KRT81/HNF1A or assessing GATA6 expression alone by IHC in samples of two independent PDAC patient cohorts (advanced PDAC n = 139 and resected PDAC n = 411) as well as in 57 matched primary tumors and their corresponding metastases. RNAseq-based expression data of 316 resected PDAC patients was analyzed for validation. Results: Transcriptional subtypes widely overlapped in both marker panels (χ 2   p < 0.001) but switched during disease progression in up to 31.6% of patients. They had a modest impact on the patients’ prognosis in both cohorts, with longer overall survival (OS) for patients with KRT81−/HNF1A+ or GATA6+ tumors but better progression-free survival (PFS) and disease-free survival (DFS) in patients with KRT81+/GATA6− tumors treated with palliative or adjuvant gemcitabine-based chemotherapy. RNAseq expression data confirmed the findings. Conclusions: Transcriptional subtypes have differential responses to palliative and adjuvant gemcitabine-based chemotherapy and may change during disease progression. Both employed subtyping marker panels are equivalent and may be used to inform clinical therapy decisions.