The Cancer Code: A Revolutionary New Understanding of a Medical Mystery

by Jason Fung

INTRATUMORAL HETEROGENEITY

Does cancer contain the necessary genetic diversity to allow evolution? The answer is a resounding yes, as shown by the Cancer Genome Atlas.

The genetic diversity of ITH is a key enabler of tumor evolution, allowing natural selection to proceed through branched-chain evolution.

BRANCHED-CHAIN EVOLUTION

How does tumor evolution proceed? The SMT proposed that cancer evolved linearly. Cancer cells added mutations one at a time, until the cells acquired all the hallmarks needed to become cancer. This theory predicted that a single disruption, such as a drug or engineered antibody, could break the entire chain and cure cancer. A fantastic story, but now known to be wrong for most common cancers.

Figure 12.1: Tree growth as an example of branched-chain evolution.

Cancer is also now known to follow branched-chain evolution. Figure 12.2 illustrates how ITH and branched-chain evolution allow greater survival.

When cancer encounters an obstacle—for example, the administration of chemotherapy that kills 99 percent of cancer cells—only a single subclone of cancer need survive in order to repopulate the ...

A tree with multiple branches needs only a single hole to grow through a fence. Figure 12.2: Genetic heterogeneity and branched-chain evolution of cancer...

M. Gerlinger et al., “Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing,” New England Journal of Medicine 366 (2012): 883–92. Figure 12.3: Cancer evolution over time shows evidence of branched-chain evolution.

THERAPEUTIC IMPLICATION

The recognition that cancer continually evolves through both time and space via branched-chain evolution was a major break from the preceding decades of cancer orthodoxy. This has two major implications for cancer treatment and explains much of the lack of progress in oncology. A single targeted treatment is unlikely to be successful. Cancers can evolve to be resistant to treatment.

SELECTIVE PRESSURE

Cancer’s deep evolutionary roots run way past the origins of mankind, right back to the origin of multicellular life on earth. So, what is cancer? The simple answer is this: Cancer is a unicellular organism, but in order to transform itself from a normal cell in a “society” with rules for cooperation to a unicellular existence, it had to undergo hundreds or thousands of genetic mutations.

The next question to answer is: what guided the selection ...

cells evolve toward a clearly defined destination, unicellularity, with the resolute purpose and tenacity of a bloodhound.

why does cancer evolve toward a form that will ultimately kill itself?

First, cancer behaves like a unicellular animal. Bacteria grown in a Petri dish will continue to grow until the food runs out. They make no effort to reduce growth in response to the obviously depleting food resources because each individual cell is concerned about only its own growth at that time.

Second, cancer largely strikes older adults, long after the reproductive phase of life. Genes that increase cancer risk are still passed on to the next generation.

But if cancers are constantly and independently mutating, then how did they end up so similar, sharing all the same hallmarks? There are two possibilities: convergent evolution and atavism.

CONVERGENT EVOLUTION

But if each of the millions of cancers in history are evolving independently, how can they be so similar? It cannot be the environments, because they are utterly different.

Figure 12.4: Forward evolution of cancer—sequential addition of mutations.

So, how can we explain the remarkable coincidence? As Paul Davies considered the problem, he was struck by the way cancer is “very deeply embedded in the way multicellular life is done.”

The roots of cancer lie in our evolutionary past. Perhaps cancer was not a forward-looking evolutionary process, but a backward-looking one.

AT...

A human tail is an example of atavism, the reappearance of an ancestral trait after it has been lost for many generations. (The word is derived from the Latin word atavus, meaning “ancestor.”) Webbed fingers are another kind of atavism. While rare, atavisms occur regularly. But how did they develop? There are two general possibilities: Hundreds of mutations come together to form a tail from scratch (de novo). This is a forward evolution, the addition of a new trait to an existing structure. The biological plan for a tail already exists but is normally suppressed. Losing the suppressive mechanisms allows the tail to manifest. This is a backward evolution, the uncovering of an ancient but hidden trait.

Imagine an art classroom where each child produced an identical picture of a flower—same size, same colors, same flower. Did every child just independently decide to paint the identical picture? Hardly. It’s more likely that the picture was a paint-by-numbers kit that each child simply took it out of the box. In cancer’s case, is it more likely that every cancer in history decided to evolve all the hallmarks independently, or that these hallmarks already existed and needed only to be uncovered?

Figure 12.5: Progression from single-cell organism genes through multi-celled organism genes to cancer.

The atavistic theory proposes that cancer is a reversion to an evolutionarily earlier format, the unicellular cell.

This atavism is essentially a backward, not a forward, evolution. It is a return to an earlier surviving version.

During the evolution to multicellularity, new control systems were added to the original program to ensure cooperation and coordination.

Single-cell organisms grow, are immortal, move around, and use glycolysis. As multicellularity evolved, new genetic instructions were added to stop growth, make cells mortal, stop cells from moving around, and change energy generation to favor OxPhos.

You can train a tiger to tolerate humans and eat from its bowl. But if it becomes angry and forgets its training, the tiger reverts to being a wild animal.

If these more recently added genetic controls are damaged, then the ancestral traits reassert themselves. That is how a normal cell completes the cancerous transformation (see Figure 12.5).

This theory makes the wild, but correct, prediction that cancer is a common, not a rare, event, as it is relatively simple to damage controls instead of building hundreds of coordinated new mutations in forward convergent evolution.

Cancers all reach the same destination (unicellularity) by following a guided path (atavism) rather than a random walk (convergent evolution). Convergent evolution is about addition; atavism is about subtraction.

Why is cancer found in all multicellular animals? Why can every cell in the body become a cancer? Why are cancers so common? Why are cancers so similar to one another if they developed independently? The SMT had no answers, but atavistic evolution explains much of cancer’s behavior. Still, what was the initial selection pressure that transformed a cooperative cell from a multicellular organism to a competitive single-cell organism? Now that we know what cancer is, we can ask a new question: what causes cancer?

13 CANCEROUS TRANSFORMATION

THE NEW EVOLUTIONARY paradigm of cancer was finding completely unexpected answers.

Cancer is, improbably, a backward evolution, or atavism, toward the single-cell organism ...

When these unicellular traits become exposed, the result is cancer. Is there any proof for this? Recent research...

According to this theory, cancer cells should express more ancient unicellular genes and fewer genes from the more recent multicellular period. This is exactly what studies are now finding. The number of cancer mutations peaks exactl...

Figure 13.1: Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors.

The answer is yes. Cancer preferentially expressed the ancient unicellular genes of phylostrata one through three. The genes representing the transition from unicellular to multicellular life, phylostrata four through eleven, were the most consistently and noticeably disrupted in cancer. These were the precise genes responsible for enhancing intracellular cooperation.2

Cancer progressively demolishes the existing regulatory structures to reactivate its “genetic memory” of being a single-cell organism.

The tumor suppressor gene p53, the most important in human cancer by far, is found in more than 50 percent of all cancers. The BRCA1 gene, well known to increase risk of breast and ovarian cancer, is also a tumor suppressor gene.

Conceptually, cancers evolve toward the same unicellular destination: the stem cell.