NEW YORK (GenomeWeb) – A new study suggests that pancreatic cancer evolution does not always involve gradual, sequential mutations, but may also include spates of rapid and complicated rearrangements to the tumor genome.
Researchers from Canada, the UK, the US, and Spain developed a new informatics method called CELLULOID to take a closer look at DNA copy number patterns and genomic rearrangements in tumor samples from more than 100 individuals with pancreatic ductal adenocarcinoma. Their analyses, reported today in Nature, unearthed examples of punctuated evolution in many of the tumors, including apparent chromothripsis events and new driver mutations that seemed to occur side-by-side.
"These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumors," senior author Steven Gallinger — a researcher affiliated with the Ontario Institute for Cancer Research, Mount Sinai Hospital, and the University Health Network — and his co-authors wrote.
Past studies have highlighted the rampant copy number changes found in some pancreatic cancer genomes. Nevertheless, the recurrent, sequential gene mutations accumulating over time in the pancreatic intraepithelial neoplasms that precede some pancreatic cancer cases suggest genomic instability is a consequence of these cancers, instead of a driving force in tumor formation, the authors noted.
To delve into these questions further, the team used the CELLULOID tumor ploidy and copy number analysis tool to assess whole-genome sequence data for 107 primary or metastatic pancreatic ductal adenocarcinoma tumors. The team saw signs of polyploidy in 45 percent of the tumors. These pronounced ploidy changes were particularly common in tumors containing TP53 gene mutations.
Using hints from the broader mutation profiles for the polyploidy tumors, the group also began trying to untangle the timing of gene mutations, polyploidizations, and copy number changes in the tumors. While the researchers traced most mutations back to a point prior to tumor polyploidy, for example, many of the most dramatic copy number gains and losses seem to have occurred later on in tumor formation. Based on such patterns, the study's authors argued that copy number changes can quickly accumulate after a polyploidization event, likely spurring on pancreatic cancer progression.
The team also uncovered evidence of chromothripsis events in roughly two-thirds of the tumors — a result the group verified by analyzing an independent set of 84 more pancreatic cancer samples.
Some of the alterations appeared to follow predictable patterns, such as the presence of recurrent chromosome 18 gains in tumors with SMAD4 gene losses. Even so, the sequence of mutations often did not appear to match those predicted from models based on pancreatic intraepithelial neoplasm samples alone.
"If chromothripsis is indeed the transforming event in some tumors, as our data suggest, a single event could thus confer a cell with both invasive and metastatic properties," Gallinger and co-authors wrote. "In this scenario, there would be a very short latency period between the birth of the invasive clone and the ability of that clone to metastasize."