Integrative genomics sheds new light on metastatic cancer
A new study from the University of Michigan Comprehensive Cancer Center has just been released that represents an in-depth look at the genomics of metastatic cancer, as opposed to primary tumors. This work involved DNA- and RNA-Seq of solid metastatic tumors of 500 adult patients, as well as matched normal tissue sequencing for detection of somatic vs. germline variants.
A good overview of the study at the level of scientific layperson can be found in this press release. It summarizes the key findings (many of which are striking and novel):
- A significant increase in mutational burden of metastatic tumors vs. primary tumors.
- A long-tailed distribution of mutational frequencies (i.e., few genes were mutated at a high rate, yet many genes were mutated).
- About twelve percent of patients harbored germline variants that are suspected to predispose to cancer and metastasis, and 75% of those variants were in DNA repair pathways.
- Across the cohort, 37% of patient tumors harbored gene fusions that either drove metastasis or suppressed the cells anti-tumor functions.
- RNA-Seq showed that metastatic tumors are significantly de-differentiated, and fall into two classes: proliferative and EMT-like (endothelial-to-mesenchymal transition).
A brief look at the data
This study provides a high-level view onto the mutational burden of metastatic cancer vis-a-vis primary tumors. Figure 1C from the paper shows the comparison of mutation rates in different tumor types in the TCGA (The Cancer Genome Atlas) primary tumors and the MET500 (metastatic cohort).
Here we can see that in most cases (colored bars), metastatic cancers had statistically significant increases in mutational rates. The figure shows that tumors with low mutational rates “sped up” a lot as compared with those primary tumor types that already had high rates.
Supplemental Figure 1d (below) shows how often key tumor suppressor and oncogenes are altered in metastatic cancer vs. primary tumors. TP53 is found to be altered more frequently in metastatic thyroid, colon, lung, prostate, breast, and bladder cancers. PTEN is mutated more in prostate tumors. GNAS and PIK3CA are mutated more in thymoma, although this finding doesn’t reach significance in this case. KRAS is altered more in colon and esophagus cancers, but again, these findings don’t reach significance after multiple correction.
One other figure I’d like to highlight briefly is Figure 3C from the paper, shown below:
I wanted to mention this figure to illustrate the terrifying complexity of cancer. Knowing which oncogenes are mutated, in which positions, and the effects of those mutations on gene expression networks is not enough to understand tumor evolution and metastasis. There are also new genes being created that do totally new things, and these are unique on a per tumor basis. None of the above structures have ever been observed before, and yet they were all seen from a survey of just 500 cancers. In fact, ~40% of the tumors in the study cohort harbored at least one fusion suspected to be pathogenic.
There is much more to this work, but I will leave it to interested readers to go read the entire study. I think this work is obviously tremendously important and novel, and represents the future of personalized medicine. That is, a patient undergoing treatment for cancer will have their tumor or tumors biopsied and sequenced cumulatively over time to understand how the disease has evolved and is evolving, and to ascertain what weaknesses can be exploited for successful treatment.