Friday, January 2, 2015

Hopkins is wrong. Role of bad luck in cancer not shown!

Amidst much fanfare, Johns Hopkins issued a news release, dated Jan. 1, 2015, under the banner, “Bad Luck of Random Mutations Plays Predominant Role in Cancer, Study Shows" The subtitle to the banner is, "Statistical modeling links cancer risk with number of stem cell divisions.”

Whoever wrote the Hopkins news report doesn't seem to understand that the subtitle contradicts the title. The title implies that the authors have proven an assertion (i.e., that bad luck causes cancer). The subtitle indicates that they have only established an association (i.e., there is a statistical link between cancer incidence and random mutations occurring as stem cells divide). It seems like a quibble, but there is an immense conceptual gulf between a "link" and a "cause". It's easy to find a correlation, but it's hard to prove a causal role. In many cases, correlations simply disappear when the original data is reanalyzed with different analytic methods, or when some of the original assumptions are changed, or when new data is obtained, or when information from some other study provides better results that support an opposing hypothesis.

The Hopkins researchers reviewed the literature to find, "the cumulative total number of divisions of stem cells among 31 tissue types during an average individual’s lifetime." These numbers for the different tissues, correlated closely with the risk of cancer occurring in those tissues. Having arrived at the correlation, "using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65 percent." Of the 31 tissues they studied, the tumor incidence in 9 of the tissues did not fit their "bad luck" correlation. Tumor incidence in these tissues, according to the news report, must come from some other source, such as environmental carcinogens. The 22 tissues that fit their model were deemed the "bad luck" tumors.

The bad luck hypothesis is not new. Cancer researchers have been trying to titrate the various suspected causes of cancer for decades. In the 1970s, when there was a large push to find chemicals in the environment that cause cancer, it was widely accepted that about 85% of cancers were caused by environment agents; 15% were caused by other things, such as genes, and this last 15% would also include "bad luck" mutations. These numbers were based on statistical inferences from data on the geographic variations in cancer incidence, looking at how the types of cancers occurring in populations changed in different locations on earth and in response to identified carcinogens.

Back in the early '70s, there was an awareness of the special place of "rare cancers" in the discussion. The common cancers (i.e., skin, lung, colon), were all presumed to be caused by environmental toxins (e.g., UV light, cigarettes, food and water contaminants, chronic infections, etc). More than 90% of the burden of cancer in the U.S. is accounted for by just a handful of cancer types (namely, basal cell carcinoma of skin, squamous cell carcinoma of skin, bronchogenic lung cancer, adenocarcinoma of colon, adenocarcinoma of breast, adenocarcinoma of prostate, adenocarcinoma of pancreas, ovarian carcinoma, esophageal cancer, and maybe one or two others). There are over 6,000 different kinds of cancer. All but a half dozen or so of these 6,000 varieties of cancer are rare, accounting in the aggregate for fewer than 10% of the tumors occurring in humans. Many of the rare cancers have well-studied patterns of inheritance. Because there are so many known inherited rare cancers, we tend to assume (perhaps incorrectly) that the bulk of rare cancers are caused by inherited genes (i.e., not caused by random mutations occurring in individuals with cancer).

OK, so lessons learned through the history of cancer research seems to be at odds with the conclusions drawn by the Hopkins team. Let's ignore history, for a moment. Here is a list of present-day concerns that should, at the very least, tone down the conclusions reached by the Hopkins study.

1. There are animals with much higher stem cell renewal than that seen in humans. Consider the whale. Whales have tons of intestines with trillions of dividing cells. If stem cell division and random mutation account for cancer, then you would expect every whale to be chock full of intestinal cancers. They are not. Please, spare me the argument that whales are different from humans and the two species cannot be compared. If you assert that random mutations in the DNA of stem cells is the cause of cancer, then your assertion should apply equally to any organisms that contains DNA and stem cells.

2. Carcinogenesis (i.e., the biological process that leads to cancer) is known to be a multi-step phenomenon. Mutation may be the first step, but many additional steps, leading to cancer, must occur, sometimes playing out over decades. In a multi-step process, you cannot expect any single event (e.g., a random bad luck mutation) to account, by itself, for the incidence of cancer.

3. There is a high cancer rate in mice and rats, both relatively short-lived animals. Wouldn't you expect a low accumulation of random bad mutations in animals that only live a year or two? The rapid evolution of cancers in short-lived animals (i.e., weeks or months) suggests that something in addition to random bad luck mutations must account for carcinogenesis in these animals.

4. Biological systems are complex, and causation is seldom a meaningful concept when many events contribute to a single observed phenomenon. For example, random mutation may occur more frequently in tissues with rapidly dividing stem cells, but rapid division of cells may occur in response to some toxic effect or chronic condition that causes a subpopulation of cells to die. Hence, rapid division of stem cells may be the result of some other "cause". Likewise, chronic toxicity and subsequent stem cell renewal in various tissues may result from higher rates of activation of carcinogens (i.e., metabolism) in those tissues. Hence, stem stem cell renewal may be tightly coupled with a variety of biological influences other than "bad luck".

In summary, the correlation observed by the Hopkins scientists is interesting, and it probably deserves further investigation. But the assertion that "bad luck" causes most human cancers is pretty much meaningless, at the moment.

- Jules J. Berman

p.s. The topic of today's blog is covered in depth in several of my published books, particularly Neoplasms: Principles of Development and Diversity, and expanded in my next blog post.

tags: johns hopkins, cancer news, bad luck, data repurposing, opinion, criticism, carcinogenesis, rare cancer, rare diseases, cancer incidence, comparative carcinogenesis, Jules J. Berman, Ph.D., M.D., cancer research, new findings, mutation rate, rebuttal, stem cell, stem cell renewal