Monday, January 5, 2015

Is cancer just bad luck? Part I. Known risk factors are poor predictors

Cancers are a highly unpredictable set of diseases, representing a fundamental problem in understanding causation that Tomasetti and Vogelstein address in a recent paper in Science ("Variation in cancer risk among tissues can be explained by the number of stem cell divisions", 2 Jan 2015, Vol 347 Issue 217).  This paper has gotten a lot of notice, both approving and not.  A bit of history might be helpful.

Cancers are due to cell proliferation gone wrong, that is, not obeying the constraints on division and differentiation of their particular tissue.  The idea has been that this is due either to exposure to some environmental risk factor, including something to do with lifestyle, or to genetic predisposition.  Both seem to be true at the population level, with, for example, breast cancer associated with age at first birth or whether women breast feed or not, number of children, alcohol consumption, and so forth, and with clear genetic risk factors, like some BRCA1 and 2 risk alleles.  In populations, people who smoke are more likely to get lung and other cancers, people with HPV cervical cancer, and so on.  But this doesn't mean that everyone who smokes, or has particular genetic risk allele, will get cancer, and that's the issue.  

Even if a risk factor is know, that doesn't explain the immediate cause of a tumor, at the cell level.  That cause is gene(s) misbehaving, causing the cell to divide at an inappropriate time.  So the idea for decades had been that environmental agents that stimulated cell division put cells at risk of incurring a mutation, and environmental mutagens caused those changes, which were the ultimate or final causes of cancer.  Hence, the search for 'cancer' genes.  

In the old days (the 1990s!), direct searches for genes were generally not possible, with a few exceptions where viruses seemed to change genes in a cancer-causing way.  But some cancers seemed to be clearly familial, that is, inherited in a Mendelian way in families.  They were statistically predictable, but with the problem that the risk depended on whether you inherited a risk gene, and we could only make a probabilistic statement about that.  A few lucky breaks showed that finding such genetic mutations was possible.  Specific inherited cancer risk-genes was first and most clearly demonstrated for a couple of childhood tumors.  Most notably, perhaps, was the eye cancer, retinoblastoma.  A fortuitous chromosomal deletion allowed the responsible gene to be identified, which was rare at that time for biomedical genetics, that was largely confined to predicting risk with no understanding of nor ability to test the actual causal gene.  There were a few others with similarly lucky discovery.

However, when genotyping on a genome-wide scale became possible, the idea was clearly that we could search the entire genome for locations that were co-transmitted or associated with a given type of cancer.  There have been many different methods, and a few clear successes.  The hallmark, and indeed one of the first genomewide screens to yield a major risk factor, was the finding that the BRCA1 and BRCA2 genes could, when experiencing one of several particular mutations, lead to a very high lifetime risk of cancer.  This was done in large, multi-generational families, but the success spurred methods to search more generally in populations (that we now call GWAS or other types of searches).  The BRCA discovery led to the rampant genomewide approach that we have seen in the recent 15-20 years.  The idea underlying this work has been the idea of finding risk variants that are strong enough, if not to be transmitted clearly in families, at least consistently affect risk, and this has been extended to basically every trait someone could get a grant to study.

But even when BRCA causation was found, there were important questions.  Those inheriting a high-risk BRCA mutation and who did in fact get breast (or ovarian) cancer, did not get those diseases until mid- to late life.  The lifetime risk was very high indeed, and some unfortunately got separate cancers in each breast.  Yet this was not the rule.  So, if the gene 'caused' the cancer, why did it take so long to do it?  An obvious answer is that it was environmental factors.  Also, by far most cancers do not segregate in families in Mendelian fashion the way BRCA mutation effects can, and indeed relatives only share slightly excess risk.  Even cases are at only slightly elevated risk than controls for most cancer-related gene mapping results.  One would think that the final risk might be due to the additional contribution of environmental factors.

Epidemiological studies of environmental risk factors for cancer have identified the major ones -- smoking, asbestos, exposure to UV light and X-rays, exposure to some chemicals used in agriculture and so on.  So, many (especially environmental epidemiologists who don't have a stake in the competition for genomic funding) have argued that if genomic variation isn't a good predictor, environmental variation must be!  But after extensive work, environmental factors don't explain all causes of any given cancer, either, nor can exposure history reliably predict cancers -- only a small minority even of smokers goes on to develop lung cancer, e.g.  And, indeed, unlike smoking and a few others, most environmental associations and candidate factors aren't clear mutagens or promoters.  So what's going on??

Why don't environmental or genetic risk factors explain all the risk?
This is the problem Cristian Tomasetti, a mathematician, and Bert Vogelstein addressed.  Vogelstein was one of the pioneers of the search for somatic mutation. That is, the mutational change that makes a cell misbehave need not have been inherited, but have been generated during the person's life. Vogelstein years ago applied a particular technique to show that tumor cells contained a particular kind of mutation (called 'loss of heterozygosity') that was not found in non-cancer cells from the same individual, but often was found in particular genome regions for a given type of cancer (in particular, colorectal cancer).  That was rather clear evidence (and there was evidence from a growing number of other researchers, too) that cancer was indeed a 'genetic' disease, but not just due to inherited variants.

Tomasetti and Vogelstein point out that current data suggest that only 5-10% of cancers are caused by heritable factors, and environmental factors can't explain the wide disparities in risk of cancer in different tissues.  They wondered how much cancer is caused by chance and how much by environmental factors.  By "chance" they mean things that just happen to go wrong during the DNA copying that occurs during cell division, which is when a tumor gets started.  Their analysis suggests that these changes are just inherent molecular copying errors, that don't have to be induced by environmental factors.

Writing in the same issue of Science in which the paper appears, Jennifer Couzin-Frankel describes the work:
In a paper published...this week in Science, Vogelstein and Cristian Tomasetti, who joined the biostatistics department at Hopkins in 2013, put forth a mathematical formula to explain the genesis of cancer. Here’s how it works: Take the number of cells in an organ, identify what percentage of them are long-lived stem cells, and deter- mine how many times the stem cells divide. With every division, there’s a risk of a cancer- causing mutation in a daughter cell. Thus, Tomasetti and Vogelstein reasoned, the tissues that host the greatest number of stem cell divisions are those most vulnerable to cancer. When Tomasetti crunched the numbers and compared them with actual cancer statistics, he concluded that this theory explained two-thirds of all cancers.
Tomasetti and Vogelstein estimate the stochastic, or chance effects "associated with the lifetime number of stem cell divisions within each tissue."  These effects can be mathematically distinguished from environmental risk factors.  They predicted "that there should be a strong, quantitative correlation between the lifetime number of divisions among a particular class of cells within each organ (stem cells) and the lifetime risk of cancer arising in that organ."  And this is what they found, and how they determined that two-thirds of all cancers are due to chance; the changes that occur just by bad luck during DNA replication.

There are also life-history aspects of cell division that are generally consistent with this.  For example, neurons stop or at least slow down their division rates as the brain matures, while glial (supporting) cells keep dividing, and most brain cancers in adults are gliomas.  Retinoblastoma (eye cancer) risk is mainly at birth or early childhood, and retinal cells have stopped dividing after that.  But radiation treatment (an environmental mutagen) for RB has been found in the past, at least, to lead to later bone cancer, when bones are rapidly growing.

This has generated some attempts at rebuttal, which is not surprising, because many hopes as well as vested interests among geneticists and environmental epidemiologists are threatened by the finding.  But in fact, based on work and then-current ideas we ourselves were involved in back in the 1970s and 80s, the current kerfuffle is a reflection both of culpable misunderstanding, ignoring of long-standing evidence, wishful thinking, and looking away from some facts that raise challenges even for the 'new' explanation of cancer causation.  We'll discuss that tomorrow.


Michael Finfer, MD said...

One thing that we have gleaned from the BRCA mutation carriers is the idea that the group of diseases commonly referred to as ovarian cancer probably do not arise in the ovaries. This is not the final word. It is still a work in progress, but when those women began to have their tubes and ovaries removed prophylactically, we began finding tiny primaries in the tubes, not the ovaries, so the serous carcinomas, the disease associated with BRCA mutations, probably arise in the Fallopian tubes. The other common diseases previously included in ovarian cancer are now suspected to arise in endometriosis and thus the endometrium.

While "ovarian cancer" is still a phrase in common usage, even amongst physicians, it is probably a misnomer.

Ken Weiss said...

Thanks for this information. It's not surprising to learn these things, as they seem consistent with what happens every time we look more closely at a subject! Interesting to me is that while I believe the BRCA genes are ubiquitously expressed, they are really only closely associated with a few tumors. As they are supposed to be mutation-repair genes, one would expect more effects, and that seems to point to other genes playing fundamental roles, or something like that. Also, many tissues have hugely more cells than breast ductal tissue (not to mention Fallopian tubes or ovaries) so why are those tissues so vulnerable? Interesting, whatever the answer.