Next generation sequencing reveals pancreatic cancer’s secrets

Pancreatic cancer is a killer, being the fourth leading cause of cancer death and a shocking overall five-year survival rate of less than five per cent.

It is also notoriously difficult to treat, with survival remaining roughly the same for the last 50 years despite advances in cancer treatments.

Now a collaboration of Australian and international researchers have conducted a large scale genomic study of pancreatic cancer and have revealed some of the key mutations that drive it.

They also found that even tumours that appear to be very similar can have a very different mutation profile, suggesting they might require different treatments.

The study, which was published this week in Nature was a collaboration between Professor Andrew Biankin from The Kinghorn Cancer Centre at Sydney's Garvan Institute of Medical Research and St. Vincent's Hospital and Professor Sean Grimmond from the Institute for Molecular Bioscience (IMB) at The University of Queensland.

This analysis represents the first report from Australia's contribution to the International Cancer Genome Consortium (ICGC), which brings together the world's leading researchers to identify the genetic drivers behind 50 different cancer types.

The study involved a cohort of over 140 patients with primary operable, untreated pancreatic ductal adenocarcinoma (PDAC), which accounts for over 90% of pancreatic cancer.

Samples of their tumour cells were taken which then underwent genome-wide sequencing using next generation sequencers, including the new Ion Torrent Personal Genome Machine at Grimmond’s lab.

“We found over 2,000 mutated genes in total, ranging from the KRAS gene, which was mutated in about 90 per cent of samples, to hundreds of gene mutations that were only present in 1 or 2 per cent of tumours,” said Grimmond.

“So while tumours may look very similar under the microscope, genetic analysis reveals as many variations in each tumour as there are patients.

“This demonstrates that so-called 'pancreatic cancer' is not one disease, but many, and suggests that people who seemingly have the same cancer might need to be treated quite differently.”

A deeper understanding of the genetic profile of pancreatic cancer will aid researchers in understanding how the cancer functions and is able to overwhelm the body’s normal defence mechanisms, as well as giving leads on how to treat the cancer in each specific individual.

Professor Biankin said such individual genetic diagnoses and treatments represent the future of healthcare.

“In this study, we found a set of genes, the axon guidance pathway, that is frequently damaged in pancreatic cancer patients and is associated with a potentially poorer outcome for those patients. It is a new marker of pancreatic cancer that can be used to direct prognoses and treatments.

“'Personalised medicine', where the molecular profile of a patient is matched to the best treatment, is the way the world is moving for many diseases, not just cancer.

“The challenge now will be in moving from population healthcare and a 'one drug fits all' model to personalised healthcare. First we must take the time to develop the necessary genetic knowledge and implement health systems to translate that knowledge effectively.”

Professors Biankin and Grimmond acknowledged the vital assistance of the Australian Pancreatic Cancer Genome Initiative, a network of more than 20 hospitals and research institutions Australia-wide, with over 200 members – surgeons, pathologists, nurses and researchers – that all contributed to the project.

They also collaborated with colleagues from the Baylor College of Medicine and The Methodist Hospital Research Institute in Texas, the Ontario Institute for Cancer Research, Johns Hopkins University in Maryland, the University of California San Francisco, the University of Verona, the Cambridge Research Institute and the Sanger Centre in the UK.

The ICGC project is being funded through $27.5 million from the National Health and Medical Research Council of Australia (NH&MRC), its largest-ever single grant.

The paper was published in Nature.