Clinically Relevant Pancreatic Cancer Subtypes Identified

Researchers have sequenced 100 pancreatic ductal adenocarcinomas (PDACs) from patients, identifying four subtypes with distinct clinical features. Each subtype, defined as stable, locally rearranged, scattered or unstable, had a distinct pattern of genomic rearrangements affecting genes previously implicated in pancreatic cancer, including TP53 and CDKN2A. The study also identified two new candidate driver mutations of pancreatic tumorigenesis: KDM6A and PREX2.

The work by United Kingdom and Australian researchers may pave the way to better classifications of pancreatic tumors, and to guide treatment selection as well as new drug development for the disease. With pancreatic cancer being the fourth most common cancer type diagnosed in the Western world, it is also one of the most lethal types of cancer with a median survival of about 6 months. Each of these new subtypes may, in the future, may be treated differently. 

The study is published in the February 26, 2015 issue of Nature.  

Nicola Waddell, a biostatistician at the QIMR Berghofer Medical Research Institute in Brisbane, Australia, Andrew Biankin, PhD, of the University of Glasgow, Sean Grimmond, PhD, of the Institute for Molecular Bioscience at the University of Queensland in Australia, and colleagues conducted both whole-genome sequencing and copy-number variation analysis on these patient samples. The work is a more detailed effort that extends a prior study of 142 pancreatic tumors from the International Cancer Genome Consortium that included researchers from Australia, the UK, and Canada--some of whom participated in the current study, and was also published in Nature.

In the current study, researchers compared sequences from the tumor and matched normal tissue samples to identify pancreatic tumor mutations, rearrangements, and copy number changes.

Almost 75% of the tumors sequenced had either a chromosomal rearrangement or a mutation in TP53 (tumor protein 53), a tumor suppressor gene. About one-third of the tumors had a mutation in CDKN2A (cyclin-dependent kinase inhibitor 2A), a gene that produces two proteins which function in important cell cycle regulatory pathways.

The authors were also able to track the responses of some of the genotyped patients after platinum-based chemotherapy. In this proof of concept test, the authors used the mutation and structural genetic differences to identify potential biomarkers of responsiveness to platinum-based chemotherapy, the current standard of care for pancreatic cancer.

Tumors within the unstable subclass had broad genomic instability across the entire genome and a mutational profile characteristic of cells with faulty DNA repair-suggesting that this subclass may be responsive to DNA-damaging agents. Ten of 14 of these "unstable" tumors also had mutations in the BRCA pathway, implicated in DNA repair and genomic stability maintenance, including mutations in BRCA1, BRCA2, and PALB2.

Two of five patients within the unstable subclass and a faulty DNA repair signature had “exceptional responses”-complete radiological resolution of disease-when treated with platinum-based chemotherapy. An additional two patients had partial responses. These responses to platinum-based chemotherapy were also supported by experiments with patient derived xenografts.

“Being able to identify which patients would benefit from platinum-based treatments would be a game-changing moment for treating pancreatic cancer, potentially improving survival for a group of patients,” said Biankin in a press release.

Clinical trials with a large sample size are needed to validate these potential chemotherapy biomarkers.