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Massive Cancer Genome Study Shows DNA Errors Can Lurk For Years Before Other Signs Emerge

author

Tom Hale

Senior Journalist

clockFeb 6 2020, 18:41 UTC

Color-enhanced image of a lung cancer cell dividing. Anne Weston/Francis Crick Institute (CC BY-NC 4.0)

A gigantic new project has sequenced the genomes of dozens of cancers, revealing an unprecedented look into the fundamental nature of cancer. Among the research’s many fresh insights, it revealed that the genetic glitches responsible for cancer can sometimes appear years or decades before any other signs of cancer.

The Pan-Cancer Analysis of Whole Genomes (PCAWG) project involved over 10 years of work from more than 1,300 scientists around the world. Their findings were released today in nearly two dozen papers in Nature and other Nature Research journals.

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Altogether, the project has sequenced 2,658 whole-cancer genomes from 38 different tumor types. Previous research has focused on the protein-coding regions of the cancer genome, accounting for around 1 percent of the picture, while this whole-genome analysis throws light onto the remaining 99 percent. 

Cancer is a disease of the genome caused by mutations in the DNA of a cell during its replication and division. Often these “errors” in the code are harmless and quickly resolved, but others allow the cell to divide uncontrollably. Each of these mutations leaves a “genetic fingerprint,” referred to as a mutational signature. The research was able to pinpoint many of the mutational signatures that give rise to the wild growth of cancer cells by finding the differences in the DNA sequence and gene expression between cancerous tumor cells and normal cells. 

Only about half of all the mutational signatures have known causes, triggers like tobacco smoke or radiation. However, the project can now be used to find more of these underlying causes.

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The findings suggest that many people's cancers contain on average four to five fundamental mutations that drive the cancer's growth. Another key insight was that one person's cancer genome often differs from another person's.

"The entire Pan-Cancer work is helping to answer a long-standing medical difficulty: why two patients with what appears to be the same cancer can respond differently to the same drug. We show that the reasons for these different effects of treatment are written in the DNA," Dr Peter Campbell, head of Cancer, Ageing, and Somatic Mutation at the Wellcome Sanger Institute, said in a statement.

Crucially, they also found that around 20 percent of mutations seem to be early events in a tumor’s development, often occurring years before any apparent sign of cancer can be found. Some specific examples of this include certain types of ovarian cancer and two types of brain tumors, glioblastoma and medulloblastoma.

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While that discovery might sound worrying, it could help to improve early cancer detection and deliver more effective treatments.

“We’ve developed the first timelines of genetic mutations across the spectrum of cancer types. For more than 30 cancers, we now know what specific genetic changes are likely to happen, and when these are likely to take place. Unlocking these patterns means it should now be possible to develop new diagnostic tests, that pick up signs of cancer much earlier,” Peter Van Loo, co-lead author and group leader in the Cancer Genomics Laboratory at the Francis Crick Institute, said in another statement.


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  • genome,

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  • Cancer genome,

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  • cancer genomics

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