Cancer is a disease of information, in which a cell becomes reprogrammed into a precision killing machine. In the consensus that has emerged from decades of research, this transformation is the result of approximately half a dozen genetic mutations — changes that accumulate over the years to a cell’s DNA.
For us humans these are deadly defects. But from the point of view of the cancer cell, each change is a beneficial adaptation. In a sped-up version of Darwinian evolution, the cells become fitter and fitter in their ability to compete and thrive inside the ecosystem of the body.
The first mutation might be to a gene that is responsible for controlling mitosis — how frequently a cell divides. A second mutation might turn off a gene that normally serves to rein in excessive cellular proliferation. Flooring the accelerator and cutting the brake line — that is the familiar analogy. The cell goes on to divide into two daughter cells. Each in turn divides to produce twins of its own. All, of course, inherit the same genetic instructions.
With each new generation, more mutations accumulate and these allow the grandchildren and the great grandchildren to evade other safeguards. There is a biological computer (the telomeres) that counts and limits the number of times a cell can divide. There is a mechanism called apoptosis through which dangerously deranged cells are induced to commit suicide. There are proofreading enzymes that scan and repair errors in the genome. One by one these defenses are defeated.
Through other mutations, cancer cells “learn” to produce enzymes that eat into neighboring tissue and to grow vessels into the body’s circulatory system — a source of nourishment and an avenue through which to metastasize.
The six or so abilities a cancer cell must acquire are described in a classic paper, “The Hallmarks of Cancer,” and more recently in a followup: “Hallmarks of Cancer: the Next Generation.”
The number of mutatations varies somewhat. But the hallmarks have become so widely accepted that it was jarring at first when results began to emerge from the grand effort to sequence the genomes of cancer cells. Some of them were found to have dozens or even hundreds of mutations. But how many of these were actually important? What was signal and what was noise?
A cancer cell, by definition, is one that is replicating wildly beyond control. With all the safeguards knocked out, it is also mutating like crazy. It is genomically unstable. The difficulty is separating the mutations that are actually driving the cancer from those that are carried along for the ride. As Jennifer Wapner put it last week in an article for Slate, “Sorting through a tumor to find the causative mutants is like finding the tiniest of needles in a haystack where new needles keep appearing as the haystack grows.”
A study published last week by Nature helps put the matter back into perspective. A team from Washington University analyzed 3,281 tumors representing 12 different types of cancer. The average number of driver mutations, they concluded, is between two and six — consistent with the small number implied by the hallmarks.
A single type of cancer might be driven by various combinations of mutations — there is more than one way to floor the accelerator or to cut the brakes. For patients, narrowing down the details may lead to a more effective treatment. That is the hope anyway. But that day, as Wapner laments, has yet to arrive. For most mutations, there is no drug to counteract them.
And when there is, the cancer cells often find a workaround — a mutation that allows them to achieve their Darwinian imperative in another way. Maybe that is the scariest thing about cancer: The instinct for survival that drives life itself is just as powerful in the malignant cells.
Related post: The Most Powerful Carcinogen is Entropy
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