Dr. Robert A. Nagourney, MD
IS 8% OF THE GENOME THE MISSING LINK FOR ADVANCED CANCER?
In the modern era, discoveries in human genomics get front-page coverage. Following the 2003 publication of the human genome made up of over 3 billion base pairs, there remained some nagging gaps in the DNA code that have now been solved. In a paper published in the April 1, edition of Science, a consortium of researchers report that the last 8% has been filled in. Humanity is now in possession of a 100% complete genome.
But what are the implications? First, we have to put it into context. We already had 92% of the human genome fully sequenced in 2003. For anyone who has ever looked at a photograph or watched a TV game show, once you have 92% of the data most contestants can guess the rest. More importantly, will this have an impact on the diagnosis or treatment of diseases like cancer?
The answer to the last question is likely no. The human genome has been largely sequenced with regard to areas that play into cancer for approaching 20 years. We know that there are about 1000 human cancer-related genes, 2/3 of which function as tumor suppressors (brakes) and another 1/3 as oncogenes (gas pedals) that drive tumors.
Despite our rather expansive knowledge of human cancer genomes, we do not know how to use these gene findings for therapy. This is because cancer is much more than the sum of its genes and demonstrably more complex than the DNA informatics we call genomics. Knowing the sequence of the gene does not tell you how, when, or why it will be used. A gene might be up-regulated, down-regulated, methylated, acetylated, amplified, or deleted. It is the context in which all this takes place that makes you, you.
One very clear example is the recent discovery of a treatment for patients with a mutation in the oncogene KRAS, G12C. It is a wonderful breakthrough and fully 37% of lung cancer patients with this KRAS G12C mutation responded to the new drug. However, when colon cancer patients with exactly the same KRAS G12C mutation were treated with exactly the same drug at exactly the same dose, only 9.7% responded!
Clearly, there is more to human biology than the sum of its genes.
We applaud the efforts of investigators in the Human Genome Project and believe that these studies will be of great use in the study of human evolution and human biology. Unfortunately, these discoveries, particularly the last 8% aren’t likely to affect the way we treat cancer. To understand cancer biology, we must study cancer biology, and the study of cancer biology is best done at the level of the cell. It is human tumor primary culture analyses, not genes, that will provide the answers that cancer patients need.