Whole genome sequencing redefines the mutational landscape of pancreatic cancer

Scientists from the International Cancer Genome Consortium (ICGC) have done the most in-depth analysis yet of 100 pancreatic cancer genomes. The study was recently published in Nature.

Using whole genome sequencing, the team revealed broad patterns of “structural variation”, or change, previously invisible when it was feasible to sequence only protein-coding genes (exomes, around 1% of the genome). The prior study by the same group, which examined only the exomes within the same cohort of 100 patients, showed a complex mutational landscape, as well as enormous heterogeneity among the tumours. Thousands of mutated genes were present, and a long tail of infrequently mutated genes dominated.

Moving to whole genome sequencing represented a significant step towards a better understanding of the tumor genetic landscape. In fact, ‘point mutations’ (specific errors in the chemical code of a tumor’s DNA) aren’t the only genetic mistakes that cause cancer. Errors can also occur when large bits of a cell’s DNA get moved around, copied, deleted or inserted somewhere else in the genome. This genetic shuffling is called structural variation. It can occur in different forms: genes get deleted, repeated, turned on or off, or even stitched together to make new, mutant forms. Like landmasses or ice shelves, entire chromosomes can shatter and rearrange themselves. Just as satellite images allow us to see the Earth as a whole, and zoom into the detail when we choose, whole genome sequencing allows us to view global and local DNA damage equally effectively.

The principal aim of the study was to understand the degree to which genetic shuffling is involved in the pancreatic cancer, and whether different types are related to how cancer cells behave in different patients. The results revealed something completely new: the samples could be divided into four distinct groups, based on the level and type of structural variation in each tumour’s DNA.

  1. Stable subtype (20%). These tumors exhibited a relatively low levels of DNA shuffling.
  2. Locally rearranged subtype (30%). In these tumors shuffling only happened in a particular area of the genome.
  3. Scattered subtype (36%). These tumors displayed quite a bit of genetic shuffling in lots of areas of the genome.
  4. Unstable subtype (14%). These tumors had incredibly chaotic DNA.

These concepts shed light on how the chaotic chromosomal rearrangements cause a huge range of genetic faults that are behind the disease, and provide opportunities for more personalised pancreatic cancer treatment. As an example, the study suggests which pancreatic cancer patients may benefit from platinum-based drugs – these are commonly used chemotherapy treatments, typically used for testicular or ovarian cancer. So far these drugs have had limited impact in pancreatic cancer but the researchers found that a handful of patients who had ‘unstable’ chromosome rearrangements and defects in the DNA repair pathways could potentially benefit, sometimes showing exceptional improvement.

Professors Andrew Biankin and Sean Grimmond, laboratory heads at Sydney’s Garvan Institute of Medical Research and the University of Queensland’s Institute for Molecular Bioscience (IMB) respectively, led the study. Both are now based at the Wolfson Wohl Cancer Research Centre, part of the University of Glasgow in Scotland. The Verona group was led by Professor Aldo Scarpa (ARC-NET Cancer Research Center), Professor Claudio Bassi (Pancreatic Surgery), and by Professor Giampaolo Tortora (Medical Oncology).

To see the abstract on the publisher’s website click here.

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