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

by Jason Fung

NCI, “Age and Cancer Risk,” National Cancer Institute, April 29, 2015, https://www.cancer.gov/about-cancer/causes-prevention/risk/age. Figure 6.3: Percentage of new cancers by age group across all cancer sites.

THE PHILADELPHIA CHROMOSOME

HER2/NEU

CANCER PARADIGM 2.0

Figure 6.4: Treatment – cancer paradigm 2.0 with targeted genetic treatment.

The genomic revolution was unstoppable and showed no sign of slowing. Rather, the pace of technological advance and medical knowledge was accelerating.

7 CANCER’S PROCRUSTEAN BED

In the end, patients—even incredibly wealthy and influential celebrities—must surgically remove their breasts and ovaries to prevent cancer. It would seem that our genetic wizardry was making little more progress against cancer than the breast guillotine. How did things go so wrong with the genetic paradigm of cancer?

TWIN STUDIES

A large study of the twin registries of Sweden, Denmark, and Finland concluded that the majority of the risk in the causation of cancer is not genetic. In fact, genetics accounts only for an underwhelming 27 percent of risk. The vast majority of the risk (73 percent) is environmental.

The authors concluded that “Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms.” The environment plays the principal role in the development of cancer.

The risk of developing breast cancer in patients with BRCA1 and 2 by age fifty is 24 percent for those born before 1940, but 67 percent for those born after.

The predominant problem is not the gene itself, but the environment that allows these cancerous tendencies to manifest.2 In other words, cancer growth depends upon not only the seed but also, and more importantly, the soil.

A thirty-two-year twin registry follow-up revealed that the increased risk of cancer in fraternal twins was only 5 percent; it was 14 percent in identical twins.3 Certainly, there was a genetic link to cancer, but it was hardly the overwhelming certainty it is often made out to be. Cancer is largely caused by environmental, not genetic, factors.

This becomes even clearer when we look at the changes to cancer risk when a population suddenly changes environments.

P. Lichtenstein et al., “Environmental and Heritable Factors in the Causation of Cancer,” New England Journal of Medicine 343 (2000): 78–85. Figure 7.1: Environmental and heritable factors in the causation of cancer.

ABORIGINAL POPULATIONS

Figure 7.2: Increasing cancer risk in native Canadians, 1972–1981.

Cancer rates of the native Ojibwa population rose sharply in the 1980s, coinciding with the increasing Western influence on their lifestyle.

Their gene pool would not have changed significantly over a few decades, pointing once again to the massive effect of environment, predominantly ...

J. T. Friborg and M. Melbye, “Cancer Patterns in Inuit Populations,” Lancet Oncology 9, no. 9 (2008): 892–900. Figure 7.3: Cancer incidence and patterns in Inuit populations, 1950–1997.

MIGRANT STUDIES

R. G. Ziegler et al., “Migration Patterns and Breast Cancer Risk in Asian-American Women,” Journal of the National Cancer Institute 85, no. 22 (November 17, 1993): 1819–27. Figure 7.4: Changing breast cancer risk with migration, 1983–1987.

J. Peto, “Cancer Epidemiology in the Last Century and the Next Decade,” Nature 411, no. 6835 (May 17, 2001): 390–95. Figure 7.5: Effects of migration on cancer rate, 1988–1992.

The genetic paradigm of cancer had focused myopically on the “seed,” but it was both the seed and the soil and their interaction that determined cancer risk.

THE HUMAN GENOME PROJECT AND BEYOND

THE PROCRUSTEAN BED

So, the real question now became: how many genetic mutations were needed for cancerous transformation? Two? Three? Four?

By 2006, there were unsettling signs that cancer mutations were more complex than first imagined.

Within the same patient, metastatic cancer differs genetically from the original tumor. One site of metastasis may differ from another by twenty or more genetic alterations.25 This degree of genetic heterogeneity was completely unexpected. Even within the same tumor mass, cells carried different mutations. Cancers differed with respect to their gene mutations in the following ways:

Different types of cancer had different mutations.

The same type of cancer in different patients had dif...

The same cancer in the same patient had different mutations in the primary tumor compared...

The same cancer in the same patient had different mutations at differen...

The same cancer in the same patients in the same tumor mass had ...

The hard truth became one the research community couldn’t deny: cancers were far, far more different gen...

8 THE DENOMINATOR PROBLEM

BY THE 2000s, hundreds of potential cancer-causing genes had been identified. Everywhere researchers looked, there were more oncogenes and tumor suppressor genes. Presumably, a single mutation in any one of the normal growth-controlling genes could cause cancer. So why wasn’t everybody getting cancer? There is a common issue in surveillance studies called the denominator problem. Suppose we analyze one hundred great baseball players and discover that every one of them has a liver. We might conclude that having a liver makes you a great baseball player. But this is a logical fallacy, because many people with livers are not great baseball players. This is the denominator problem. Out of all people with a liver, how many are great baseball players compared to the many who are not?

If we take one hundred cancer samples and find that all one hundred have genetic mutations, we might conclude that having genetic mutations is the key to developing cancer. But that conclusion is not logically warranted because we are st...

The Cancer Genome Atlas pinpointed plenty of mutations, but the important question not asked was: how many normal cells carry the very same mutations in the cancerous pathways but do not develop into cancer?

This evidence points to a simple yet stunning fact: the premise that a single mutation in an oncogene or tumor suppressor gene is the origin of most cancer growth is far too simplistic. The SMT had ignored the denominator problem. But there was another problem still. The genetic mutations were a proximate, rather than a root, cause of cancer.

PROXIMATE VERSUS ROOT CAUSES

For any disease, understanding the root cause (known as the etiology) is the basis fo...

The root cause of disease is what we generally consider the “real” cause of the event in the first place, and it often requires higher-level thinking to determine.

For example, liver failure is caused by fibrotic scarring known as cirrhosis. This information is true, but not very useful. Rather, we want to know what causes the cirrhosis.

Figure 8.1: Root cause, proximate cause and outcome.

Whereas treating the root cause is successful, treating the proximate cause is not (see Figure 8.2). How does this apply to cancer? Genetic mutations were only the proximate cause of cancer. What was driving those mutations to occur?

Figure 8.2: Root cause, proximate cause and outcome contrasting plane crash and cancer.

In almost all human disease, treating the root cause, not the proximate cause, is the key to success.

But why does cancer develop these mutations? What is the driving force behind these mutations? Cancer paradigm 2.0 suggested that these mutations were accumulated purely by chance (see Figure 8.3). The known root causes of cancer (chemicals, radiation, and viruses) increase mutation rates, allowing some to randomly aggregate into cancer.