Thursday, November 3, 2011


Because I’m enrolled in a tumor registry at OHSU, where all of my surgeries have been, my melanoma genome has been thoroughly parsed. The results: I don’t have the two most common mutations found in advanced melanoma: BRAF and KIT genes. However, I do have what’s known as the NRAS Q61K mutation, which occurs in about 15% of melanomas. NRAS may be down the melanoma pecking order, but because the RAS family of mutations are found in about a third of all human cancers, it’s still of keen interest to drug developers.

That’s what a broken piece of DNA can do for you.
Therapeutics that target mutant RAS genes directly are in various stages of clinical trials, but have so far not been especially successful. This is painstaking science. Researchers hope that as the genetics behind all forms of cancers become better understood, they will succeed at developing targeted drugs that can fix faulty genetic machinery. As I’ve observed in previous posts, the BRAF mutation in melanoma is now treatable by Zelboraf, which was approved by the FDA earlier this year.

Melanoma is one of the most challenging solid cancers to work with because it has such a high rate of mutation. A tumor that starts with one or two mutations can, over time, accumulate dozens or even hundreds of mutations. Oncogenic NRAS is thought to activate a series of signal pathways in cells that are crucial for the control of growth signals, cell survival and invasion of melanoma cells. Scientists are working on an approach that curtails NRAS activity, which could prove to be a sensible way to inhibit melanoma growth. If they succeed, it will take years and millions of dollars for them to shepherd a new drug through the regulatory gauntlet.
Genes control how a cell functions, including how quickly it grows, how often it divides, and how long it lives. To control these functions, genes produce proteins that perform specific tasks and act as messengers for the cell. This is why it’s essential that each gene have the correct instructions or “code” for making its protein, so that the protein can perform the proper cellular function.
My melanoma presumably began when one or more genes in a single cell were mutated by excessive UV exposure, creating an abnormal protein or no protein at all. The information provided by an abnormal protein is different from that of a normal protein, which can cause cells to multiply uncontrollably and become cancerous. This usually takes years or even decades, which is why the genetic mutations that can occur in childhood from excessive sun exposure usually don't manifest themselves as melanoma until middle age—sort of like smoking and lung cancer.
At this stage, knowing that a major culprit in my melanoma genome is NRAS Q61K is little more than an intellectual curiosity. It’s not like I can see it or touch it. This knowledge about mutations means more to the investigators running the tumor registry, who I hope can put the data they’ve collected from 5000 or so patients to good use. Basic science like this isn’t sexy, but may yield clues for where investment in applied cancer research should be directed.

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