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Researchers Identify Molecular Subtypes of Pancreatic Cancer Through Genomic Analyses

NEW YORK (GenomeWeb) – An Australian-led research team has molecularly characterized pancreatic cancer, divvying the disease into four subtypes.

As reported today in Nature, the University of Queensland's Sean Grimmond and his colleagues analyzed more than 450 pancreatic ductal adenocarcinomas to identify nearly three dozen recurrently mutated genes that affect 10 biological pathways. Further, expression analysis clustered these samples into four subtypes: squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX). Each subtype, they noted, was enriched for certain mutations and effects on certain pathways.

"These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development," Grimmond and his colleagues wrote in their paper.

Some 49,000 people a year are diagnosed with pancreatic cancer, and its five-year survival rate is only about 7 percent, according to the National Cancer Institute.

Grimmond and his colleagues analyzed 382 pancreatic cancer samples from the Australian Pancreatic Cancer Genome Initiative using a combination of whole-genome and deep-exome sequencing alongside copy-number analysis and RNA sequencing. These samples were largely treatment naïve and included pancreatic ductal adenocarcinoma (PDAC) as well as adenosquamous, colloid, PDAC associated with intraductal papillary mucinous neoplasm, and a few rare acinar cell carcinomas.

In these, the researchers uncovered 23,538 high-confidence coding mutations, 7,377 of which they verified using orthogonal approaches. They also identified 21,208 high-confidence genomic rearrangements.

To be able to better uncover coding driver mutations, Grimmond and his colleagues folded 74 previously published pancreatic cancer exomes into the mix.

From all these, the researchers identified 32 significantly mutated genes using OncodriverFM, 22 of which were also identified by MutsigCV2 or were also supported by HOTNET2 analysis. These mutated genes, Grimmond and his colleagues further found, largely affected 10 molecular mechanisms, and included activating KRAS mutations, disruption of G1/S checkpoint machinery, disruption of TGF-β signaling, and disruption of histone modification, among others.

The researchers also uncovered some 50 regions of recurrent gains and 73 regions of loss.

Unsupervised clustering of RNA-seq data sorted 96 pancreatic tumors with high epithelial content into four groups. These same four subtypes were also present in a set of 232 pancreatic cancers that had been analyzed using array-based mRNA expression profiles.

The researchers dubbed these subtypes squamous, pancreatic progenitor, immunogenic, and ADEX.

Ten biological processes could distinguish these four subtypes, the researchers noted, and each of the subtypes were linked to specific histological characteristics.

For instance, they noted that the squamous subtype was linked with adenosquamous carcinomas, while the immunogenic subtype was linked with mucinous non-cystic adenocarcinomas and carcinomas arising from intraductal papillary mucinous neoplasms.

Four core gene programs — involved in inflammation, hypoxia response, metabolic reprogramming, TGF-β signaling, and more — could distinguish the squamous subtype from the others, the researchers said. This subtype was further linked with TP53 mutations and increased expression of TP63∆N and its target genes as well as with the hypermethylation and downregulation of genes involved in pancreatic endodermal cell-fate determination, which leads to a loss of endodermal identity.

Transcription factor networks that are "pivotal" for determining pancreatic cell fate — such as ones including PDX1, HNF1B, FOXA2, and FOXA3, among others — define the pancreatic progenitor subtype, Grimmond and his colleagues reported.

Likewise, transcriptional networks, though ones active later in pancreatic development and differentiation, also define the ADEX subtype. Those networks include the transcription factors NR5A2, MIST1, and RBPJL as well as their downstream targets, which are important in acinar cell differentiation and regeneration. They also include genes associated with endocrine differentiation. 

Finally, the immunogenic subtype is marked by many of the same features of the pancreatic progenitor subtype, the researchers said, but also by immune infiltrate. They noted that immune gene programs like B cell signaling pathways, antigen presentation, CD4+ T cell, CD8+ T cell, and Toll-like receptor signaling pathways were linked to this subtype.

"The novel immunogenic subtype of pancreatic cancer is characterized by specific mechanisms that can potentially be targeted using immune modulators, and testing in clinical trials is encouraged," the researchers added.

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