Cancers arise due to mutations in the genomes of individual cells within the body. To understand the disease – and treat it more effectively – we need to better understand the mutations and the particular mutated genes that convert a normal breast cell into a breast cancer cell.

The BASIS project focused on a particular class of breast cancers, called ‘oestrogen-receptor-positive’, which account for two-thirds of the cases diagnosed. The researchers catalogued the thousands to tens-of-thousands of mutations present in each of more than 400 complete breast cancer genomes.  

From these mutations, the project was able to generate an essentially complete catalogue of the genes that become drivers of breast cancer when they are mutated – identifying 93 different breast cancer driver genes. In other words, the presence of one or more of these mutated genes in the genome of an individual breast cell takes that cell down the road to becoming a breast cancer. Blocking or altering the function of any of these mutated genes could mark the way for new treatments by reversing their effects.

“To achieve that essentially comprehensive catalogue of driver genes is really a major milestone for breast cancer, and for other cancers,” says Sir Mike Stratton, Director of the Wellcome Trust Sanger Institute and coordinator of the project. Thanks to the computing power available at institutes such as Sanger, and the techniques of rapid whole genome sequencing, for the first time scientists are getting a more comprehensive view of the disease.

More complex than first thought

“We have sequenced the whole genome of these breast cancers and that is important, because it basically allows us to see all types of mutation in all parts of the genome,” he says.

All these mutated driver genes have the feature that they cause a cell to grow more like a cancer cell, but the way in which they do that differs from gene to gene. “And what we’re finding from the sequencing is that it’s actually a very heterogeneous, complex disease.”

It is not simply a question of matching a cancer to a single mutated gene in a patient – there could be up to 10 driver mutations operating in a single cancer which means multiple different combinations of these mutated cancer genes.

There are many processes through which genes become mutated; some external, such as cigarette smoke’s role in lung cancer or sunburn’s contribution to skin cancers; and some internal, through metabolic malfunctions in individual cells.

The wealth of data acquired by BASIS allows researchers to sift through the patterns of mutation in hundreds of cases and extract “signatures” that could be attributable to different processes. The project has found 18 such signatures, providing vital clues to the ultimate causes of different types of breast cancer, and to potential treatments.

A real turn-off (or on)

These driver genes, and their mutations, are the veritable breadcrumbs that science can follow to develop new drug candidates to treat the resulting cancers – because essentially some of these genes, or at least their proteins, have been turned on. The next step is to find medicines to turn them off (or the other way round in cases when the mutation has turned the genes off).

Drugs are usually developed to turn proteins off, the project coordinator explains, but if they are already turned off, what happens then?

“We know that genes and their proteins work in pathways, so even if a particular gene and it’s protein have been switched off, we can look down perhaps at the next protein in that pathway, which may be working overtime to compensate, and think about making a drug to switch that one off instead,” he suggests.

International effort pays off

The EU-funded project took place as part of the Breast Cancer Working Group within the International Cancer Genome Consortium (ICGC), a huge initiative involving stakeholders from all over the world. The Working Group has catalogued 560 cancer genomes in total, thanks to three smaller projects, but the 400 from BASIS make up the lion’s share.

“This study is basically the largest number of whole genomes that have been sequenced for any cancer type thus far,” notes Stratton.

Twenty years ago, cancer was essentially a “black box”, he says. But now, thanks to the huge efforts of projects like BASIS, science is heading towards more or less a complete description of these key elements in how cancers develop.

The next step, he says, is to “let the intellects and the creative minds of our scientists loose”, to analyse this huge resource of data and turn new knowledge into potential treatments.