Molecular Subtypes of Pancreatic Cancer Identified
Pancreatic tumors can be divided into 4 classes based on molecular and genetic features, researchers show. The findings reveal differences in the development of different subtypes of pancreatic cancer that could lead to new therapeutic targets and individualized therapy.
Peter Bailey et al performed an integrated genomic analysis of 456 pancreatic ductal adenocarcinomas (PDACs) and their histopathologic features using a combination of whole-genome and deep-exome sequencing, with gene copy number analysis. RNA expression profiles were used to identify tumors subtypes, which were associated with differences in histopathology and survival.
In an article published online in Nature on February 24, Bailey et al describe 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, transforming growth factor beta, Wnt, NOTCH, SLIT-ROBO (SRGAP2), the G1/S transition, SWI/SNF (SMARCA4), chromatin modification, DNA repair, and RNA processing.
Gene expression profiles defined 4 subtypes: squamous (S), pancreatic progenitor (P), immunogenic (I), and aberrantly differentiated endocrine–exocrine (ADEX, A) (see figure).
Bailey et al found that squamous tumors frequently contain TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, and hypermethylation of genes that determine pancreatic endodermal cell fate. Patients with this tumor type had the shortest median survival time (13.3 months).
Pancreatic progenitor tumors were characterized by upregulation of genes involved in early pancreatic development (FOXA2 or FOXA3, PDX1, and MNX1). These tumors expressed the apomucins MUC5AC and MUC1, but not MUC2 or MUC6. Patients with these tumors survived a median time of 25.6 months.
ADEX tumors upregulated genes that regulate networks involved in KRAS activation and exocrine (NR5A2 and RBPJL) and endocrine differentiation (NEUROD1 and NKX2-2). Transcriptional networks that characterized exocrine and endocrine lineages at later stages were upregulated, rather than 1 or the other as in during normal pancreatic development. Patients with these tumors survived a median of 23.7 months.
Immunogenic tumors upregulated signaling networks that contributed to immune suppression. The immunogenic subtype of pancreatic tumors shared many of the characteristics of the pancreatic progenitor class, but was associated with infiltration by immune cells. Associated immune gene programs included B-cell signaling pathways, antigen presentation, CD4+ and CD8+ T cells, and Toll-like receptor signaling pathways. The CTLA4 and PD1 acquired tumor immune suppression pathways were also upregulated in these tumors. Patients with this tumor type survived for a median 30 months.
The findings are important because pancreatic cancer is the fourth leading cause of cancer death in Western societies, and projected to become the second within a decade. Fewer than 5% of patients survive for 5 years after diagnosis.
Advances in therapy have not greatly affected overall outcome, but can provide notable benefits for undefined subgroups of patients. The findings of Bailey et al might help identify patients most likely to respond to particular therapies.
Andrew Biankin (University of Glasgow), one of the authors of the article, told the BBC News “This is the most comprehensive analysis of the blueprint of pancreatic cancer. It reveals what makes these cancers tick and which ones may be vulnerable to particular treatments.”
For example, the immunogenic pancreatic cancers could be susceptible immunotherapies, wrote the BBC news.
Leanne Reynolds, the head of research at Pancreatic Cancer UK, told the BBC News “the findings mean that in the future, the right patients can be given the right treatment at the right time”.