The Cancer Genome Atlas (TCGA), a comprehensive program that used sequencing to understand the genomic landscapes of 33 different tumor types, published its results Thursday in almost 30 papers in a half dozen different Cell Press journals.
The PanCancer Atlas represents an "amazing collaboration," Li Ding told BioWorld, "that allows us to understand the tumor as an ecosystem."
That ecosystem analogy is true across several different dimensions of the work. The papers collectively go far beyond cataloging genomic alterations, and give new insights into the interplay of different somatic and germline mutations, how specific mutations play out on the background of unique cell types, and how the tumor and its microenvironment interact for better or for worse.
Those insights, in turn, will enable the design of more thoughtful and comprehensive strategies for fighting back. "Knowing that information," Ding said, "will really help us to design better treatment options."
Ding is one of the lead scientists from TCGA and a corresponding author on several of the papers published Thursday.
As the clinical sequencing of tumors took off, it became clear very quickly that many tumors are chock full of mutations – but that targeting most of those mutations was an exercise in futility because they were so-called passenger mutations, a consequence rather than a cause of out-of-control cell growth. The search for driver mutations has been an organizing principle of targeted therapy, and one of the accomplishments of the PanCancer Atlas is to report new findings on almost 300 such driver mutations.
Many of those mutations themselves had already been identified as drivers. But by using unbiased "database discovery," the team was able to identify almost 60 entirely new driver genes, while other drivers were linked to additional tumor types.
For the development of novel targeted therapies, "those will be the 300 genes that pharmaceutical companies will be [focusing] their efforts on," Ding predicted.
With the advent of genomics, there have been predictions that, ultimately, mutation type would become more important than the anatomical location of a tumor in guiding treatment decisions.
The PanCancer Atlas results give new insights into the interrelationship between mutations and locations. More than a quarter of the driver genes that the TCGA consortium identified in the papers published today are important in more than one type of cancer, and "when we go into precision medicine, we will treat patients based on their mutations," Ding said.
That said, she added that "the old-fashioned way of pathology-based classification is still very useful. That's why we studied 33 cancer types – they were based on their location."
By looking at the gene clusters that were active in cells with shared driver mutations, the scientists discovered that beyond anatomical location, the cell of origin is an important determinant of tumor behavior.
The cell of origin is related to anatomical location, but cells with the same developmental roots can end up in different organs. For example, cancerous squamous cells can show up as bladder, lung or head and neck tumors. Such squamous cell-derived tumors will behave in similar ways and respond similarly to treatment across different anatomical locations.
So far, the concept of mutation over location has had its greatest clinical success with the 2017 approval of checkpoint blocker Keytruda (pembrolizumab, Merck & Co. Inc.) for microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors regardless of their anatomical location.
In the 13 years since TCGA launched its project, none of the changes clinical oncology has seen has been more transformative than the advent of cancer immunotherapies such as Keytruda, which have been described as "cancer's penicillin moment" – the moment when it became clear that in principle there could be broad-spectrum curative agents for the entire disease class.
MSI-H tumors have high levels of tumor-specific antigens, called neoantigens, that make them highly visible to the immune system. In the data published today, the authors took a more general look at mutations in pathways that would affect the production of neoantigen, either directly – fusion proteins can be a direct target of immune responses – or indirectly, because they affect processes such as DNA repair that result in higher neoantigen load.
Knowing that a patient has a defect in a homology-directed repair pathway gene such as BRCA1 or the ATM kinase, Ding said, "will affect the treatment options."
With the publication of the PanCancer Atlas, cancer genomics is certainly not at its end. The advent of single-cell sequencing has opened up additional ways to look at tumors in greater depth, as have various other -omics technologies such as transcriptomics and proteomics.
But already, Ding said, "we were so lucky to see this work from the beginning."