New Gene Study Unravels Cancer's Secrets
Cancer is a genetically driven disease, and a mother lode of new genetic data on dozens of different cancers is promising to break open fresh avenues of prevention and treatment.
Nineteen out of 20 cancers now can be tracked back to one or more specific genetic mutations, based on data gathered from in-depth sequencing of thousands of whole-cancer genomes, researchers say.
"We can now identify in more than 95% of patients at least one genetic change that's biologically responsible for the tumor, and in many patients five to 10 or more of these causal mutations, which we call driver mutations," said project co-chair Peter Campbell. He's head of cancer, aging and somatic mutation at the Wellcome Sanger Institute in England.
On average, cancer genomes contain four to five driver mutations, researchers report.
This knowledge will help researchers and doctors develop and choose from precise treatments targeting the specific mutations that are causing cancer in individual patients, Campbell said.
These findings take us "one step further down the road of understanding all the complexities of cancer," said Dr. William Cance, chief medical and scientific officer for the American Cancer Society.
"Ultimately, we want to make a cancer therapy precise for that person's individual cancer," he said. "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."
A shift of focus
Prior to this research, doctors were able to detect one or more genetic drivers of cancer in only about two-thirds of patients, Campbell said.
That's because previous genetic research into cancer focused solely on the exome -- the portion of a person's DNA that encodes proteins, said Dr. Lincoln Stein, head of adaptive oncology at the Ontario Institute for Cancer Research in Toronto.
"That's a mere 1% of the whole genome," said Stein, a member of the project. "Assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 1,000-piece jigsaw puzzle when you're missing 99% of the pieces, and there's no puzzle box with a completed picture to guide you."
This project -- the Pan-Cancer Analysis of Whole Genomes Consortium -- analyzed 2,658 whole genomes of cancer samples across 38 types of tumors. Such analysis includes all the ways DNA and RNA influence our personal biology.
The first results appeared Feb. 5 in six papers published in the journal Nature.
Campbell said the data show why two patients with the same type of cancer who get the same treatment can have completely different outcomes, with one dying and the other surviving.
How genetics and lifestyles play a part
It all comes down to how different each person's cancer genetics are compared to other patients', and how those genetics have been influenced by events over a lifetime, Campbell said. Mutations come into play, as well as factors like smoking, sun exposure or obesity.
"We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer," Campbell said. "Some of these processes reflect the wear and tear of aging. Some reflect inherited causes. Some reflect the lifestyles that people have engaged in. All of these shape and mold the genome during cancer development."
Throughout our lives, people accumulate genetic mutations from the simple act of living, he said. Every blood cell gains a mutation about once every two weeks on average. The important thing is to figure out which mutations are key to cancer.
The level of genetic understanding created by this project can allow doctors to "carbon date" a cancer, essentially tracking it back to the first events in a person's life that put them on the road to eventually developing cancer, Campbell said.
"Many of the tumor types we've studied in this project show that the first key events in cancer development occur often decades before the patient presents with a tumor, sometimes even as far back as childhood," he said. "It shows that the window for opportunity for early intervention is much wider than we might have expected before doing this work."
The quest for precision medicine
By building on this base of genetic data, researchers hope that one day a doctor will be able to feed a patient's cancer genetics and lifestyle factors into a computer and come up with precise cures for their disease.
"The difficulty with preventing and treating cancer is that there are so many pathways that are involved in its creation," Cance said. "I think of cancer as a Darwinian phenomenon, where the cells can constantly change and survive."
But these researchers found that while mutations contribute to cancer in a multitude of ways, there are still about the same number of genes that cause cancer and ways that people develop it.
"Although we greatly expanded the number of mutational events that contribute to cancer, we didn't expand in any dramatic fashion the number of cancer-related genes or cancer-related pathways," Stein said. "We found the same pathways that had been identified, but many more ways to change those pathways."
Using existing targeted therapies and ones still to come, it becomes possible to "more accurately diagnose what changes have occurred in a patient's tumor, identify the dysregulated pathways in that patient, and assign that patient to the therapy most likely to be effective and least likely to have toxic effects," he said.
That day isn't here yet because genetic sequencing and computer processing costs remain too expensive to build up the sort of comprehensive genetic data that's required, Campbell said.
"Whole-cancer genome sequencing won't be available tomorrow in your average commercial provider, but there's every reason to think within a matter of years it will more accessible than it is now and much more widely used," Campbell said.
The U.S. National Cancer Institute has more about cancer genetics.
SOURCES: Peter Campbell, Ph.D., head of cancer, aging and somatic mutation and senior group leader, Wellcome Sanger Institute, Hinxton, Cambridgeshire, England; William Cance, M.D., chief medical and scientific officer, American Cancer Society; Lincoln Stein, M.D., Ph.D., head, adaptive oncology, Ontario Institute for Cancer Research, Toronto; Feb. 5, 2020, Nature
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