Study Challenges Current View of Pancreatic Cancer Evolution

Roxanne Nelson, BSN, RN

October 20, 2016

A new study challenges current beliefs about how pancreatic cancer develops and may also help to explain why this tumor type is one of the most lethal. It is often diagnosed when already advanced, and then most patients have a grim prognosis.

Previous research based on analyses of precursor pancreatic intraepithelial neoplasm lesions has led to the current view that the disease develops through a specific sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4). The current view holds that the progression to cancer is gradual because each alteration is acquired independently.

But the new study suggests that what happens is actually quite the opposite.

Using newly developed informatics tools, Canadian researchers have found that the genetic alterations believed to cause the disease may all occur at once.

Rather than follow a gradual and accepted mutation order, the events are more simultaneous rather than sequential, and they may also include an outpouring of rapid and complicated rearrangements to the tumor genome.

The study, conducted by researchers from the Ontario Institute for Cancer Research (OICR) and University Health Network's Princess Margaret Cancer Centre, Toronto, was published online October 12 in Nature.

While these findings are early and preliminary, lead author Faiyaz Notta, PhD, an OICR fellow principal investigator at the Princess Margaret Cancer Center, pointed out that this work really begins to "reconcile why much of the effort that has gone to detect pancreatic cancer early has not really panned out."

Although it can't be proven yet, Dr. Notta feels that their paper also begins to reconcile why pancreatic cancer metastasizes so rapidly.

"As the saying goes, 'early is too late' in pancreatic cancer," Dr Notta told Medscape Medical News. "The implication of our data is that very small invasive clones are probably metastatic, and if early detection programs are to succeed, they will need to find very small lesions, potentially at the preneoplastic level."

Another implication of these findings involves the use of targeted therapy, and that is a very exciting component of future endeavors, Dr Notta said. "We find that the DNA rearrangements in these tumors affect genes that are targetable in a good proportion of cases."

But that said, it is yet unknown whether these events denote a type of biomarker, or some kind of underlying resistance mechanism. "Because this disease is so aggressive and chemoresistant, I'm leaning towards the latter," he said. "Either way, we can now begin to elucidate the pathways to combat this resistance — if that is the case — because we can identify the underlying event that has caused it."

Study Details

Pancreatic cancer is slated to become the second leading cause of cancer-related death in a decade, and the biological basis of its aggressive nature is largely undefined, the authors note.

They developed and validated a new informatic tool called CELLULOID, which estimates tumor ploidy and copy number from whole-genome data, and used it to assess 107 primary or metastatic pancreatic ductal adenocarcinoma tumors.

Findings showed that 45% (48/107) of tumors displayed changes in copy number that were consistent with polyploidization. These ploidy changes had a particularly high incidence in tumors containing TP53 gene mutations.

A sensitive algorithm, termed ChromAL, was also developed to differentiate chromothripsis (when up to thousands of clustered chromosomal rearrangements occur in a single event in localized and confined genomic regions) from localized gradual events that accumulate over time.

It showed evidence of chromothripsis events in about two thirds of the tumors (65.4%, 70/107), and the same result was observed in an independent genome cohort (60%) of 84 additional pancreatic cancer samples.

"If chromothripsis is indeed the transforming event in some tumours, as our data suggest, a single event could thus confer a cell with both invasive and metastatic properties," Dr Notta and his coauthors write. "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.

"This supposition is consistent with the observation that 80% of pancreatic cancer patients present with advanced disease at diagnosis," they add.

Funding sources for this study include grants to the Pancreatic Cancer Sequencing Initiative program from the OICR, through support from the Ontario Ministry of Research and Innovation and the Canada Foundation for Innovation, among others.

Nature. 2016;538:378-382. Abstract

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