Genomic Analysis Reveals New Pancreatic Cancer Subtypes

Genomic Analysis Reveals New Pancreatic Cancer Subtypes
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Researchers at the Ontario Institute for Cancer Research (OICR) and the University Health Network (UHN) have discovered a new way to classify subtypes of pancreatic cancer, and have distinguished five distinct subtypes based on molecular properties.

A better understanding of the disease groups may lead to new treatment options and improved clinical outcomes for this lethal disease. This new classification system is based on a study that has recently been published in Nature Genetics.  It represents the most comprehensive analysis of the molecular subtypes of pancreatic cancer to date.

Pancreatic cancer was historically categorized by physical characteristics, such as size and location of the tumor, and whether it had metastasized. However, these researchers performed a detailed genomic and transcriptomic analyses to identify five distinct subtypes of the disease: Basal-like-A, Basal-like-B, Classical-A, Classical-B, and Hybrid, each with unique molecular properties that could be targeted with novel chemotherapy treatments, biologics and immunotherapies.

“Therapy development for pancreatic cancer has been hindered by an incomplete knowledge of the molecular subtypes of this deadly disease,” says lead author Dr. Faiyaz Notta, Co-Leader of OICR’s Pancreatic Cancer Translational Research Initiative (PanCuRx). “By rigorously analyzing advanced pancreatic cancers—which is the stage of disease that most patients have when they’re diagnosed—we were able to create a framework. This will help us develop better predictive models of disease progression that can assist in personalizing treatment decisions and lead to new targeted therapies.”

Notta is referring to the genetic signatures of individual pancreatic cancer patients in the study. By creating and analyzing a database that contains each unique genome, it was possible to isolate and identify the genes most likely to be involved in the cancer’s development. Pancreatic cancer is often caught in the later stages because patients are often asymptomatic, so having more genetic markers identified can increase the likelihood of catching the cancer earlier.

Previous studies have been unable to fully document the genes involved with pancreatic cancer due to the genomic instability associated with the disease.  By using an integrated, whole-genome analysis on single tumor cells, scientists were able to create a more comprehensive library of genomes. By mapping tumor genetic histories, tetraploidization (the doubling of chromosomes) emerged as a key mutational process behind these events, thus the difference in subtypes can be traced back to genomic instability.

This study is based on data from more than 300 patients with both early stage and advanced pancreatic cancer who participated in COMPASS, a first-of-its-kind clinical trial in discovery science and personalized pancreatic cancer treatment. COMPASS is enabled by advanced pathology laboratory techniques at UHN and OICR, and next generation sequencing at OICR.

“Most pancreatic cancer research is focused solely on early stage—or resectable—tumors, but in reality, pancreatic cancer is often found in patients after it has advanced and spread to other organs,” says Notta. “COMPASS allowed us to look into these advanced cancers while treating these patients, develop a better understanding of the biology behind metastatic pancreatic cancer, and shed light on the mechanisms driving disease progression.”

Previous genomic analysis studies from Dr. Notta have shown that many genetic mutations associated with pancreatic cancer are linked to cell cycle regulation. A mutated KRAS gene is a biomarker for many cancer types, as this gene has control over cell cycle division and cancer cell growth.

Interestingly, the Basal-like-A subtype, which had been difficult to observe before this study, was linked with a specific genetic abnormality. Most of the Basal-like-A tumors harbored several copies of a mutated KRAS gene which led to overexpression of the gene.  The research group hypothesizes that some of the subtypes arise from specific genetic changes that occur as pancreatic cancer develops.

Another gene the researchers have identified as a pancreatic cancer biomarker is GATA6, a gene that regulates the epithelial–mesenchymal transition (an important gene in pancreatic tissue) that also suppresses KRAS. Previous studies have suggested patients who overexpress GATA6 live longer, unless they are treated with 5-FU/leucovorin adjuvant therapy.

“This research opens new doors for therapeutic development,” says Dr. Steven Gallinger, co-leader of OICR’s PanCuRx. “We look forward to capitalizing on the promise of these discoveries, building on our understanding of pancreatic cancer subtypes, and bringing new treatments to patients with the disease.”

By isolating and focusing on specific biomarkers associated with pancreatic cancer, it is possible to develop a comprehensive list of biomarkers associated with specific cancer types, eventually developing targets these particular gene expression pathways for patients.