Massive New Genome Study Unlocks The Mysterious Secrets of How Cancers Form

Katie Ramirez
March 17, 2020

The discovery involves areas of DNA that do not directly code for the proteins that carry out cellular activities, but instead control how genes are switched on and off. Scientists have long understood that these noncoding regions play an important role in cancer, but describing that role has been formidably hard.

But the Pan-Cancer Study sequenced entire genomes, uncovering new cancer-causing driver mutations in the other 98 percent, known as non-coding genes.

Despite decades of cancer research, a frustrating dilemma plagues doctors.

This study was supported by a variety of funders - the National Institute of Health, the European Research Council, the Richard M. Schulze Family Foundation, the University of Minnesota and Mayo Clinic Partnership, Cancer Research UK, the Shannon O'Hara Foundation, Hyundai Hope On Wheels, and a research grant from Oncolytics Biotech. The study's lead author is Matthew Reyna, a former postdoctoral researcher at Princeton who is now at Emory University.

The team found about 705 mutations occurring repeatedly in the cancer genomes, hinting that these are crucial drivers for tumor growth. That means that it should be technically possible to document every genetic change that cancer can possibly induce. Cancer is a disease driven by mutations arising within our DNA, caused by environmental factors or ageing. "We're moving toward what we call a tumor-agnostic approach, meaning that we want to look more at the genetic composition of an individual's tumor rather than treating every breast or colon cancer the same way because they are that type of a cancer". "We need many more whole cancer genome sequences - which will be coming in the near future because of decreasing DNA sequencing costs".

By completing the most comprehensive study of whole cancer genomes to date, an worldwide team of scientists has garnered deeper understanding of cancer, paving the way for more effective treatment, the Wellcome Sanger Institute said on Wednesday.

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Project published 23 papers today (February 5), including several in Nature, with insights from the genomes of more than 2,600 cancers of 38 tumor types. While many studies have been conducted to understand the types of mutations that occur in cancer genomes, little is understood about their evolution and progression.

"The incredible work of the Pan-Cancer Project team that was unveiled today is the culmination of a remarkable global collaboration that has enriched our understanding and provided new ways to approach the prevention, diagnosis and treatment of cancer", said The Honourable Ross Romano, Ontario's Minister of Colleges and Universities. We show that the reasons for these different behaviors are written in the DNA. Of the mutations, about 100 fell outside the protein-coding areas of the genome. The researchers calculated that the average cancer genome has four to five active driver mutations. However, the shortcut has left out many changes that may trigger cancer development. Other genes affect the status of chromatin, or the way DNA is packaged within the cell, which can markedly impact the expression of genes.

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Most of our understanding of this process comes from the sets of genetic instructions for building the body's proteins. The results bring up new research questions on the roles of RNA processing in cancer.

The researchers said: "Our study sheds light on the typical timescale of... tumour development, with initial driver events seemingly occurring up to decades before diagnosis".

So, for the Pan-Cancer Analysis, researchers chose to sequence entire cancer genomes.

"That's a mere 1 percent of the whole genome", said Stein, a member of the project. "The next step is experimental validation". That leaves out many genes where mutations might nudge the cell into cancerous growth.

"Once you think about rare mutations, then 2,500 samples actually becomes extremely limiting", said Raphael.

The team also found human papillomaviruses, most commonly HPV16, in 19 of 20 cervical cancers cases and in 18 of 57 head and neck tumours.

Still, Raphael says he is optimistic that other researchers will follow up on the team's findings with new data and experiments. Multiple novel regions of the genome controlling how genes switch on and off were identified as targets of cancer-causing mutations.

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