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The most comprehensive map to date of the cancer genome published

No. 05c4 | 05/02/2020 | by Koh

The great hope of precision oncology is to be able to recommend effective drugs to cancer patients based on an analysis of their tumor genome. Recommendations like these must draw on careful comparative analyses based on the genome data of thousands of patients. That is the goal of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Initiative: The researchers involved, including scientists from the German Cancer Research Center, aim to use this meta-analysis of all mutations in more than 2,600 tumor genomes from 38 different kinds of cancer to clarify which mutations or patterns of mutations in genomes promote cancer initiation and growth across several types of cancer?

Sequencing of tumor genomes in the German Cancer Research Center
© Schwerdt/DKFZ

Since 2008, scientists from across the globe have been recording and documenting the characteristic mutations in the 50 main types of cancer as part of the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas. The aim of this huge project was to find out which mutations occur in the genomes of the individual types of cancer studied. More than 22,000 tumor genomes have now been decoded.

In the follow-on project launched in 2014 – the Pan-Cancer Analysis of Whole Genomes (PCAWG) – an international team of more than 1,300 researchers is now seeking to discover which genetic mutations or patterns of mutations play a role across several types of tumor. As part of this meta-analysis, they carried out a particularly thorough bioinformatic analysis of the sequencing data of more than 2,600 tumor genomes from 38 different types of cancer and subsequently compared them. The initial results obtained by the PCAWG working groups have now been published simultaneously in 23 papers in Nature and other journals.

"When cancer develops, several cell programs are out of control at the same time: Cell division is stimulated and the cells need to avoid cell death (apoptosis), breach tissue barriers, and deceive the immune system. For all these characteristic features of cancer, there is a whole pool of cancer-promoting DNA mutations from which each individual tumor can choose," remarked genome researcher Peter Lichter from the German Cancer Research Center (DKFZ), explaining the complex situation in the tumor genome. "In order to promote the development of targeted cancer drugs in a useful way, it is important to know the whole picture and to understand the impact caused by individual mutations or combinations of mutations."

DKFZ researchers made a key contribution to the International Cancer Genome Consortium (ICGC) with genome data on brain tumors in children and prostate cancer in younger men. Another German institution, the University of Kiel, was responsible for analyzing malignant lymphomas. The genome data from all three German ICGC projects were compiled at DKFZ. The genome researchers and bioinformatics scientists from DKFZ, of whom several also work at the National Center for Tumor Diseases (NCT) in Heidelberg, the Hopp Children's Cancer Center Heidelberg (KiTZ), and the German Cancer Consortium (DKTK), are now involved in several of the 16 different PCAWG working groups.

The working groups were tasked with evaluating and classifying the mutation events by looking at different aspects: Which mutations affect non-protein-coding regions of the genome? What traces do particular mutagenic influences or infectious pathogens leave in the genome? How do the tumors evolve? Which mutations make the tumor cells immortal? What consequences do particular mutations have on the expression of important proteins?

"The great hope of precision oncology is to be able to recommend a suitable, effective drug to patients in future based on an analysis of the cancer genome. In view of the enormous complexity of the mutations that we see in tumors as a whole, however, a brief glance at the genome is not enough to be able to make these kinds of recommendations. Instead, we need a complex analysis based on a comparison with the genome data of large patient cohorts too. This is beyond the means of individual research institutions – we need the pooled expertise of international research alliances such as the PCAWG consortium," explained Benedikt Brors, a bioinformatics scientist at DKFZ.

The PCAWG researchers are making all the genome data and results of their analyses available worldwide through a data portal, taking care to comply with all the relevant legal and ethical requirements.

Many of the new findings help understand the genome biology of tumor cells, and some of the results will most probably play a key role in tomorrow's precision oncology.

The findings obtained by the PCAWG researchers include the following:

  • They confirmed that each cancer genome has an average of between 4 and 5 driver mutations. These driver mutations may point the way to promising target structures for new drugs. In some cases, it would make sense to use combinations of drugs to block several of the cancer-promoting cell mutations at the same time.
  • Around 20 percent of all the driver mutations found by the PCAWG researchers can already be treated by existing targeted drugs. Conversely, that means that drugs against other cancer-promoting mutations are urgently needed. Several such substances are already in the preclinical or clinical development stage.
  • In about five percent of the cancer cases analyzed, no tumor-promoting mutations can be found in the genome. Apparently, despite the size of the current analysis, not all cancer-promoting mutations in the genome are known yet. Other (probably very rare) mutations may promote cancer initiation in ways that are as yet unknown.
  • Certain mutations inherited from an individual's parents (germline mutations) that affect fundamental cellular processes such as DNA repair have an impact on the occurrence and type of other mutations in the cells of the body and hence on the individual's cancer risk. The PCAWG researchers found inherited mutations in cancer-promoting genes in 17 percent of all the cases studied; in 4.5 percent of cases, both alleles were affected. Under certain conditions, genetic screening for common inherited mutations might be worthwhile to identify individuals with a high risk of cancer.
  • Mutations in the non-protein-coding region of the genome may also cause cancer. Mutations in the TERT promoter are a well-known example: This genetic control element decides whether a cell produces the enzyme telomerase, which may make it immortal. In 16 percent of all the tumors studied, mutations were found that affect the expression of telomerase in various ways. Beyond that, however, the consortium found few other mutations in non-protein-coding regions of the genome that are definitely linked to cancer initiation.

Peter Campbell and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium: Pan-Cancer Analysis of Whole Genomes.
Nature 2020, https://doi.org/10.1038/s41586-020-1969-6

PCAWG data portal: https://dcc.icgc.org/pcawg 

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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