Published: Tue, March 17, 2020
Sci-tech | By Patricia Wade

Cancer-causing mutations start years prior to diagnosis

Cancer-causing mutations start years prior to diagnosis

Getz and the other PCAWG steering committee members are the senior authors of the overview paper.

Previous studies focused on the 1 per cent of the genome that codes for proteins, analogous to mapping the coasts of the continents. "Whether whole-genome sequencing is ultimately the best method in the clinic remains to be seen", Cieslik says. The team discovered that only 13 percent of drivers identified in this analysis were non-coding.

"We are finding that cancer represents the far end of an enormous spectrum of change", said Campbell.

Human papillomaviruses (HPV), most commonly HPV16, was found in 19 of 20 cervical cancers cases and in 18 of 57 head and neck tumours. Jeremiah Wala and Ofer Shapira, former Beroukhim lab members, are also co-first authors, and Getz and Beroukhim are senior co-authors of this study.

One of the biggest global studies into the causes of cancer has found genetic mutations which drive the disease begin to occur long before any other signs begin to surface.

"It's really the beginning for understanding what's happening in the noncoding space with cancer", said Ben Raphael, a professor of computer science at Princeton and a senior author of the study, published February 5 in Nature Communications. "If we narrow the search enough, we might be able to generate cost-effective assays that would allow us to study a larger number of tumor samples at a lower cost", he said. Yet now, investigators at EMBL's European Bioinformatics Institute (EMBL-EBI) and the Francis Crick Institute have analyzed the whole genomes of over 2,600 tumors from 38 different cancer types to determine the chronology of genomic changes during cancer development.

Using what they describe as a "carbon-dating method", they were able to reconstruct the order in which the genomes of cancer cells started to accumulate errors and eventually carry large segments that had been scrambled or copied. "With the knowledge we have gained about the origins and evolution of tumours, we can develop new tools to detect cancer earlier, develop more targeted therapies and treat patients more successfully".

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The team found about 705 mutations occurring repeatedly in the cancer genomes, hinting that these are crucial drivers for tumor growth. Additional contributors included 22 co-authors from institutions in the United States, Canada and Europe, with contributions from the Drivers and Functional Interpretation Working Group of the Pan-Cancer Analysis of Whole Genomes project of the International Cancer Genome Consortium. Only about half of all mutational signatures have known causes. PCAWG is a collaboration between groups from the International Cancer Genome Consortium who agreed to put thousands of sets of patient genome data together and reanalyze these samples using cloud computing. The scientists discovered many more than were previously known, and found strong associations between the new signatures and specific DNA-damaging processes.

However, at this stage, the results can not be used to test for cancers in people. "Having such a large dataset enabled us to map out these signatures with much greater precision". This study now demonstrates that APOBEC3B could also be used to increase the effectiveness of new treatments that use immunotherapy to attack tumours. "DNA can be mutated in a variety of ways, from changing single bases to removing entire sections of genetic code", Haradhvala said.

The research, carried out by an worldwide team, is said to significantly improve our fundamental understanding of cancer, suggesting new directions for its diagnosis and treatment.

The project has created and made available a comprehensive resource for cancer genomics researchers, including the raw genome sequencing data, software for cancer genome analysis, and multiple interactive websites exploring various aspects of the Pan-Cancer Project data.

They gave mice highly mutated cancer cell vaccines, in the form of mutant cancer proteins, and these elicited an immune attack against their tumours as they were immediately detected as "foreign".

The cancer genome is finite and knowable, but enormously complicated.

Dr Daniel Brewer, from UEA's Norwich Medical School, told The Telegraph: "We do not know whether the cancer has just created an environment that the viruses find attractive or whether the viruses are causing the cancer". They say the results "highlight opportunities for early cancer detection".

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