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Passenger Mutations: Cancer's Backseat and Backward Drivers

By Anette Breindl
Science Editor

The current thinking about mutations in cancer cells holds that there are two types – driver mutations that are behind cancer growth because they give tumor cells a growth advantage, and passenger mutations that are along for the ride. "Historically, passenger mutations have been largely ignored," Leonid Mirny told BioWorld Today, because cancer development is seen largely as "a series of unfortunate events" in the form of accumulating driver mutations.

But in the Feb. 4, 2013, issue of the Proceedings of the National Academy of Sciences, Mirny and his team provided evidence that this dismissive attitude toward passenger mutations may be a mistake.

Mirny, who is at the Massachusetts Institute of Technology, and his team suggested that collectively, passenger mutations also have an effect on the course of cancer, and that it may be possible to use that effect to improve cancer treatment. A number of clinically observed phenomena are "hard to explain in the framework of the traditional paradigm," Mirny said. "But they follow naturally from looking at cancer progression as a balance between drivers and passengers."

The going assumption is that passenger mutations are neutral, that is, they do not affect the rate at which cells grow. And many of them are. But passengers can, in fact, be slightly deleterious to cell growth – and taken together, many slightly deleterious passenger mutations can change the growth rate of a cell and ultimately, a tumor.

The selection process itself works mainly on driver mutations. But before the advent of such a driver mutation, "cells will accumulate lots of essentially random passenger mutations."

When a driver mutation arrives, "that cell has a huge advantage" in its proliferation rate. And as it divides, it takes those passengers, or hitchhikers, along for the ride.

Mirny and his colleagues first tested, using bioinformatics models, whether it is a realistic assumption that cells can accumulate mutations that are in fact bad for them. The net result: They can – as long as the negative effects are mild.

They also analyzed cancer genomics data to look at the mutations that tumors actually have, and predict their effects. A cancer genome usually has five to 10 driver mutations, but it can accumulate tens of thousands of mutations, of which several hundred may be in protein coding regions. Even if most passenger mutations are neutral, those that affect genes are unlikely to be so. And indeed, when Mirny and his team used existing bioinformatics programs to predict the effects of such mutations, "they looked like rather damaging mutations."

Mirny said the findings suggested a new strategy for treating cancer – one that turns cancer cells' passenger mutations against them.

The key lies in the fact that passenger mutations can be only so deleterious before they become a serious problem for tumor cells. A passenger mutation that has a small negative effect on cancer cell growth can be dragged along by a driver mutation with a large positive effect. So can 20 passenger mutations.

But only as long as the cell can protect itself against those negative effects.

The work implies that cancer cells should be disproportionately vulnerable to targeting systems that buffer cells against stress.

Such an approach, he said, is "very different" from traditional approaches, because it uses evolution against tumors. Tumors can get around driver mutations by further evolving – indeed, such further evolution is the bane of many targeted therapies.

But targeting buffering systems takes advantage of evolution, by increasing the fitness cost of deleterious mutations. And one of the effects of that approach is that it cuts off cancer's escape route.

Mirny said some clinical results fit well with that idea. Cancer cells are sensitive to the inhibition of chaperone proteins, which can help mutated proteins to fold into their correct shapes – and would be expected to be more critical for cells with a higher proportion of defective proteins. "Cancers seem to be addicted to chaperones," he said, "and this might be passenger-mediated."

Drugs like Velcade (bortezomib, Millennium: The Takeda Oncology Co.), which blocks the cellular trash disposal system, may also work partly because it prevents cancer cells from getting rid of faulty proteins.

An ever-shifting balance between growth-enhancing drivers and growth-slowing passengers could also explain phenomena like tumor regression, the existence of subclinical tumors and tumor dormancy.

On the basic science side, Mirny's team's findings provide a nuanced view of what evolution itself is.

"It is counterintuitive that in an evolutionary process, you can accumulate mutations that are bad for you," he acknowledged. But the work his team has now published showed that if those mutations are not too bad for you, such accumulations are indeed possible.