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Genome Sequencing Reveals Four Pancreatic Cancer Subtypes

NEW YORK (GenomeWeb) – A genomic study appearing online today in Nature revealed four pancreatic ductal adenocarcinoma sub-types with distinct structural variations and clinical features.

The work follows from an exome sequencing study of samples from 142 individuals with sporadic pancreatic ductal adenocarcinoma who were tested through the International Cancer Genome Consortium a few years ago.

Several researchers who were involved in that study decided to do more extensive genomic characterizations of pancreatic cancer using a combination of whole-genome sequencing and copy number profiling to test samples from 100 individuals with pancreatic ductal adenocarcinoma. 

"The patients in our cohort gave their consent preoperatively," co-senior author Andrew Biankin explained in a statement, "and we have been able to track their progress, comparing their survival with the various treatments they were given."

Biankin was based at the University of New South Wales when the study was performed. He is now a cancer researcher at the University of Glasgow.

"Doing whole-genome sequencing gave us a much clearer picture than we had before," he said. "We were able to reflect our analysis onto the patients, and started to see better association between readouts, therapies, and outcomes."

Through deep sequencing on matched tumor and normal samples from the pancreatic ductal adenocarcinoma patients, Biankin and his colleagues uncovered recurrent within-chromosome rearrangements affecting new and known pancreatic cancer contributors.

Nearly three-quarters of the samples contained either somatic mutations or chromosomal rearrangements that impacted TP53 and more than a third contained mutations or structural variants involving the CDKN2A gene. The team also found hints that alterations affecting the KDM6A and PREX2 genes may play a part in driving pancreatic cancer development 

From the way tumors clustered based on shared structural alterations, meanwhile, researchers defined the so-called 'stable,' 'locally rearranged,' 'scattered,' and 'unstable' sub-types of pancreatic ductal adenocarcinoma.

Based on the nature and extent of structural glitches identified across the tumor samples, the researchers were also able to start making predictions about drug targets in these sub-types.

For instance, tumors from the unstable sub-type — named for the widespread genomic instability they exhibited — carried mutational features pointing to glitches in DNA repair and DNA maintenance pathways.

Among the 14 pancreatic cancer patients with unstable tumor genomes who were included in the study, 10 had mutational signatures associated with risky mutations involving BRCA1, BRCA2, and/or PALB2, researchers reported.

And using information from patient outcomes and patient-derived xenograft testing, they saw a trend toward elevated response to platinum-based chemotherapy for unstable tumors with the BRCA mutation signature. 

Within the locally arranged tumor subtype, meanwhile, the team found that roughly one-third of local rearrangements affected parts of the genome that contain oncogenes, pointing to the possibility of trying to target amplified oncogenes such as ERBB2, MET, or FGFR1 with inhibitors being tested in other cancer types.

The team is now gearing up to apply such insights to new clinical trials for pancreatic cancer in the UK. Based on the pancreatic cancer subtypes identified in the current study, Biankin said, "[w]e'll select those patient groups and test the targeted therapy we believe should work."