Global study maps cancer mutations in a single large catalogue

Cancer is one of the biggest killers and in 2018 an estimated 9.6 million people around the world died of the disease. In order to provide the best treatment for the disease, it is essential to uncover which mutations are driving the cancer.

In a major international collaboration named the Pan-Cancer Analysis of Whole Genomes (PCAWG), researchers from the University of Copenhagen, Aarhus University, Aarhus University Hospital and Rigshospitalet have been involved in mapping mutations in 38 different types of cancer.

The mutations have already been compiled in a kind of catalogue which is available online. Medical doctors and researchers from all over the world can now consult the catalogue and find information about a particular patient’s cancer.

“The majority of previous major studies have focused on the protein coding two percent of the genome. What we’ve done is study and analyse the whole genome, and our analyses of mutations that affect cancer genes has enabled us to genetically explain 95 per cent of the cancer occurrences we have studied by means of mutations,” says co-author Joachim Weischenfeldt, associate professor at the Biotech Research & Innovation Centre, University of Copenhagen, and the Finsen Laboratory, Rigshospitalet.

“If you know which mutations have caused the cancer, what we call the driver mutations, then you are already better positioned to tailor a treatment with the most suitable drugs or design new drugs to fight the cancer. Precision medicine is completely dependent on the mapping of driver mutations in each cancer tumour, in relation to diagnosis, prognosis and better treatment,” says co-author Jakob Skou Pedersen, professor at the Bioinformatics Research Centre and Department of Clinical Medicine, Aarhus University and Aarhus University Hospital.

The new research results are published in a special edition of the scientific journal Nature which has focus on PCAWG. It is the largest whole genome study of primary cancer so far carried out, with the analysis being performed based on material from the tissue in which the tumour originated and prior to the patient receiving any treatment.

From a handful to one hundred thousand mutations

The researchers have primarily analysed and had data on the most common types of cancer such as liver, breast, pancreas and prostate cancer. They have analysed whole genome-sequenced tumour samples from almost 2,800 patients.

Based on their analyses, they could see that there is considerable variation in the number of mutations in a cancer type. Myeloid dysplasia and cancer in children have very few mutations, while there may be up to one hundred thousand mutations in lung cancer.

However, though the number of mutations varies widely, the researchers could see that on average there were always four to five mutations that were driving the disease – the so-called drivers – regardless of the type of cancer.

“It’s really surprising that almost all of them have the same number of driver mutations. However, this is consistent with theories about how a cancerous tumour needs to change a certain number of mechanisms in the cell before things start to go wrong,” says Jakob Skou Pedersen.

In the catalogue, the researchers have divided the mutations into drivers and passengers. Driver mutations provide a growth benefit for the cancer. Passenger mutations cover all the others and are harmless. The vast majority of all mutations are passengers.

Genetics or tissue

To store and process the large amount of data, the research team has utilised cloud computing and made use of 13 data centres spread across three continents. They have had centres in Europe, USA, and Asia.

The large data set was necessary to uncover the shared and unique aspects of the different types of cancer. Today, cancer is divided according to the tissue in which the disease originates, for example breast, brain, and prostate.

The researchers found many things that were completely unique to each type of tissue. Conversely, they also found many shared traits across the tissue types. According to Joachim Weischenfeldt, there is thus a need to rethink how we approach cancer.

“Cancer is a genetic disease, and the types of mutation are often more important than where the cancer originates in the body. This means that we need to think of cancer as not just a tissue-specific disease, but rather look at it based on its genetics and which mutations it has.”

“For example, we may have a type of breast cancer and prostate cancer where the driver mutations are similar. This means the patient with prostate cancer may benefit from the same treatment as you’d give to the patient with breast cancer, because the two types share an important driver mutation,” explains Joachim Weischenfeldt.

The research results – more information

• Type of study: Whole genome analysis of tumour samples from nearly 2,800 cancer patients with the most common types of cancer (liver, breast, pancreas and prostate cancer).
• Carried out by a global network of partners including the University of Copenhagen, Aarhus University Hospital, Rigshospitalet, The Sanger Institute, The Broad Institute of MIT and Harvard, etc.
• The Danish contribution is funded by the Independent Research Fund Denmark, the Danish Cancer Society, etc.
• Read the scientific articles ”Pan-cancer analysis of whole genomes”, "Patterns of somatic structural variation in human cancer genomes" and "Analyses of non-coding somatic drivers in 2,658 cancer whole genomes". Read the complete special edition of Nature, in which the majority of the PCAWG Consortium’s results are collected and published, and read more about the PCAWG Consortium.

Contact

Professor Jakob Skou Pedersen
Aarhus University, Department of Clinical Medicine and Bioinformatics Research Centre
Aarhus University Hospital, Department of Molecular Medicine and
Mobile: (+45) 3141 8132
Email: jakob.skou@clin.au.dk

Head of Group and Associate Professor Joachim Weischenfeldt
University of Copenhagen, Biotech Research & Innovation Centre
Mobile: (+45) 6057 3080
Email: joachim.weischenfeldt@bric.ku.dk

This coverage is based on press material from the University of Copenhagen.