2. Breast cancer’s broken genes
cancer of the breast Breast cancer is the most frightening source of mortality for women but is rarely genetic, and early detection of the disease offers the best protection.
broken genes, broken lives The genetic component of cancer is because genes break during your own lifetime, more than because you inherit already broken genes.
epidemiology and relative risk The incidence of breast cancer varies across the globe in ways that implicate modern lifestyle as a major culprit.
brakes, accelerators, and mechanics Three types of things go wrong in cancer that affect the control of cell growth and division.
familial breast cancer BRCA1 and BRCA2 are the best known genes involved in breast cancer, having a major effect in some families, but they account for a only small fraction of susceptibility in the general population.
growth factors and the risk to populations New genetic methods are finding common genetic variants that increase your risk of breast cancer ever so slightly.
pharmacogenetics and breast cancer How you respond to drugs such as tamoxifen is also influenced by your genetic makeup.
why do genes give us cancer? Until recently, cancer was not a major cause of human ill health and mortality, so there has been little pressure to rid the genome of hundreds of variants that predispose to cancer.
Cancer of the Breast
The list of famous women who have had breast cancer contains some extraordinary pairings that on the face of it suggest something other than coincidence: both of Charlie’s brunette Angels, Kate Jackson and Jaclyn Smith; the American singer-songwriters Carly Simon and Sheryl Crow; similarly the Australian pop divas a generation apart, Olivia Newton-John and Kylie Minogue; the classical actresses Bette Davis and Greta Garbo; and the diametrically opposite feminist personalities Suzanne Somers and Gloria Steinem. But at a lifetime incidence of one in nine contemporary women having breast cancer, such a list is not unusual, shocking as it is.
Less well known is the fact that lung cancer is even more common in women and, given the incidence of cigarette smoking in teenage girls and twenty-something women, is likely to increase. Heart attacks are a still greater source of mortality, but breast cancer is undoubtedly the lightening rod for women’s health issues.
Chances are, everyone knows someone who has had breast cancer. If they are friend or family, we will have shared some of the ordeal, experienced secondhand some of the pain and anxiety. In all likelihood and without realizing it we all also know women who have survived. A generation ago, breast cancer carried such a stigma and was so closely associated with a death sentence that it was kept as private as possible, almost a taboo topic of discussion. Some people may have felt the disease was contagious; others may have attached shame to the symptoms, as if contracting cancer is a woman’s fault—as if conquering the physical illness were not enough to deal with.
The reality today is that the vast majority of patients will survive. Catch a small tumor early enough, and the improvements in surgical procedures, drugs, and more focused radiation therapies almost guarantee recovery. Five- and ten-year survivorship rates are on the up, and we have started to hear that refractory cases (those stubborn or resistant to control) may not be curable but are certainly manageable.
Read any of the self-help books on the topic, and you actually get the impression that surviving breast cancer can be an extraordinarily life-affirming experience. One of the best is Barbara Delinsky’s Uplift, a compendium of short testimonials on how to use a positive outlook to cope and overcome. Many are the families that have been brought closer together by sharing the ordeal. Many are the women who find an inner strength they never knew they had, or who reevaluate what really matters in their lives. Many are the new friendships that are made through membership of the sisterhood.
The book is full of vignettes ranging from the prosaic to the profound. There’s advice for padding bras and purchasing wigs, for organizing drainage tubes after a mastectomy, and for being creative with the little tattoos that oncologists use to guide their X-ray machines. There are funny stories of flat-chested daughters welcoming formerly buxom mothers to their world, and of sadly drooping older women finding new confidence in the simply fabulous shape of an implant. There is the man with a lump in his breast who presents to a clinic where he is asked to fill out pages of forms documenting the recent regularity of his menstrual cycling or early signs of menopause. And most shocking to me was the sense that so many women are afraid to tell their husband for fear that he will think less of them if they have a breast removed, as if men are that superficial!
Early detection of breast cancer generally begins with a mammogram. Next time you are in a crowd, perhaps at a baseball game or a concert, contemplate the fate of the middle-aged and older women around you. One in nine will be diagnosed with breast cancer over the next 30 years. If 1,000 of these women were to attend a clinic that day, it is almost certain that several new cases of the disease would be detected. For the most part, the diagnosis would be early enough for physicians to intervene, and the prognosis would be excellent.
Perhaps in a few cases the woman may have been able to detect a lump by self-examination; or may have experienced unusual tenderness or discharges from a nipple, that she put down—understandably—to stress or growing older. Some will have delayed making a doctor’s appointment, out of work commitments or denial. One thing we do know, though, is that the more advanced the tumor, the larger it is, and the more time it has had to spread out of the breast, the worse are the prospects.
Of the 1,000 women, statistics indicate that about 70 would be called back for follow-up consultation. A mammogram is a low-intensity X-ray of the front and side of the breast, designed to reveal abnormal densities of cells. For the most part, these turn out on closer examination to be just a normal aspect of the breast tissue. In fact, particularly in women under the age of 40, there is typically so much density that it can obscure tumors that are present: It is thought that about ten percent of early breast tumors are missed on mammograms. More accurate procedures such as ultrasound and magnetic resonance imaging will quickly tell the doctors that 60 of the possible cases actually had a benign explanation.
Of the ten out of each thousand women whose situation looks dire enough that they are next referred for biopsy, only three or four will in fact have a cancer. Two-thirds of these will be early enough that they will almost certainly be cured. So the screening of 1,000 women will likely save the life of a couple of them, at the expense of several months of distress for as many as 100 others, while it may have missed a case as well. There is also the issue of whether the energy of the X-rays themselves can induce cancer. While this risk is miniscule for a single scan, it is incremental, so annual mammograms starting in the thirties are no longer recommended. One every few years starting at menopause seems a reasonable compromise.
Broken Genes, Broken Lives
Cancer touches every one of our lives in one way or another, seeming to show little care or concern for whom it attacks. There does not seem to be much we can do about preventing it, aside from eating more carefully and avoiding smoking. Perhaps because of the visceral nature of the disease that so clearly arises inside our bodies, unlike an infection transmitted by sex or perhaps an insect bite, cancer is commonly regarded as a genetic problem.
We’re told it is often hereditary, and this is a source of particular worry when common experience reveals that a couple of relatives in the extended family have had cancer. But since it is so common and so diverse, in most cases coincidence is a more likely explanation than inheritance. In fact, relative to the other major maladies of our time, cardiovascular disease, diabetes, asthma, and depression, cancer is the least attributable to a common set of genetic factors. Yet it certainly involves defective DNA. It is natural to ask, then, why would evolution tolerate our genes causing so much suffering?
The short answer is that it really doesn’t. There just aren’t a lot of differences mulling around in the gene pool that cause cancer. Rather, cancer is a collection of diseases that all have some fundamental things in common—most basically, cells grow out of control. Control of the growth and division of cells is so complex, that inevitably it goes wrong in most individuals at some point in their life.
Similarly, for most of us, regulating our personal finances is so complex that inevitably some combination of debt, kids, and taxes puts us under financial stress that threatens to get out of control, and sometimes does. Certainly there are intrinsic reasons why some people are more susceptible (either to cancer or bankruptcy) than others, but for the most part it is things breaking in our own lives that cause the loss of control. In the case of cancer, the breaking of genes is the primary problem, more so than inheriting broken genes from our parents.
So, why should our genes break so often? The short answer here is that they really don’t: It is the sheer scale of the thing that matters. There are millions of cells in each of our bodies, and every time one cell divides, just a handful of mistakes are made in the copying of the DNA. Humans should be so lucky to design a machine that makes one mistake in every billion operations. It only takes a couple of mistakes, namely mutations that change one letter of the DNA code into another, to push a cell along the winding and inevitable road to cancer.
It is somewhat pointless then to talk about eradicating, or even preventing, cancer. All we can do is contain it, and hopefully fix it before it does too much damage in each individual case. Containing it includes minimizing the number of mistakes made, for example, by reducing exposure to carcinogens such as tobacco and ultraviolet radiation. But it also means ensuring that adequate health care and timely screening are provided so that active interventions can be pursued.
In fact, probably the greatest risk factor for cancer, and the one we can choose as a society to do most about, has nothing to do with the underlying biology, but rather concerns socioeconomic status. Cancer survival is directly related to quality health care as well as the decision to take advantage of that health care, for example, by pursuing early breast and prostate cancer screening options. Without adequate health insurance this does not happen. Without a certain level of trust and confidence in the medical profession, this does not happen, and in this respect race is also a factor. There might well be racial differences in predisposition to certain cancers, but if there are, the impact of the genetics is likely to pale in comparison to the differences in utilization of the health care.
Epidemiology and Relative Risk
One of the great heroes in the history of cancer research and public health is the little-known English physician Janet Lane-Claypon. In the first quarter of the 1900s, having become one of the first women to receive both M.D. and Ph.D. degrees, she carried out a remarkable series of studies that went a long way toward founding the field of epidemiology. One of these demonstrated the nutritional superiority of human breast milk over cow’s milk and led to her being commissioned by the British Ministry of Health to conduct the first large case-control study on the causation of cancer.
After surveying 500 cancer patients and 500 matched cancer-free women she was able to conclude, presciently, that such factors as age at menopause, age at first pregnancy, number of children, and breast-feeding have a significant impact on the incidence of breast cancer. Furthermore, she was also the first to demonstrate that early surgical intervention significantly improves long-term survival. All this in half a career, since marriage in her late 40s to a colleague in the Ministry meant, by bureaucratic rule, that she must abandon her position. Such was the fate of all too many women scientists in the middle of the last century.
The epidemiological risk factors identified by Janet Lane-Claypon are now thought to reflect lifetime exposure to estrogen and other hormones involved in female reproduction. With better nutrition, girls are reaching puberty earlier, and breast maturation commences at a younger age. Delayed first pregnancy and failure to breast feed both increase estrogen levels in the breast, as does prolonged time to menopause. Similarly, prolonged post-menopausal hormone replacement therapy is now widely thought to contribute as much as 20 percent of the risk of breast cancer in older women.
Risk is a difficult concept to get our heads around. Typically it refers to the extra fraction of people who have the disease because of some risk factor. It is formulated as the ratio of the prevalence in the at-risk group to the prevalence in the population at large. A ratio of 2 means that the risk is increased 100 percent and a ratio of 1.01 means that it has increased one percent. It is far from trivial to establish that a relative risk of one percent is significant. Suppose that there really aren’t any factors that make anyone in your town or subdivision or city block more or less likely to get cancer. Over a 20-year period, perhaps 500 of the 10,000 people in the neighborhood are stricken with the disease. If you arbitrarily split the community into two groups of 5,000 people each—say those who live in even-numbered houses, “the evens,” and those in the odd-numbered houses, “the odds”—then you would expect that 250 each of “evens” and “odds” would have cancer. However, it would not be particularly surprising to find 230 “even” and 270 “odd” patients, just because of random sampling. In this hypothetical case, there is more than a five percent difference in the frequency of cancer in the “evens” and “odds.” So, on the face of it, there is a relative risk that large of living in an odd-numbered dwelling and getting cancer.
Then, if you look at enough behavioral patterns, maybe you will discover that orange juice consumption or attendance at the opera is slightly less common in the cancer group than you would expect given the frequency of these activities in the whole community. After the statistical epidemiologists crunch the numbers, there might well be a significant correlation between not drinking orange juice or not enjoying high culture, and contracting cancer. In fact, it is all but inevitable that correlations like this arise by chance, usually at pretty marginal significance levels, but they translate into fairly large apparent risk factors. The only way around this is to replicate the study in different populations, and then to try to work out the mechanism that causes the correlation.
Of course, there is no guarantee that a strong correlation really implies causation in any case. If you look at a map of incidence of all types of cancer in America, painting states with low incidence red and relatively high incidence blue, it is virtually indistinguishable from the political map of George W. Bush’s America. Voting Republican causes a lot of things, but I’m pretty sure that offering protection from cancer is not one of them.
Brakes, Accelerators, and Mechanics
To see why cancer is a disease of the genes but not generally a hereditary disease, we need to understand how defective genes cause cancer and what makes them defective. Cancer is basically a collection of diseases, since the things that go wrong in brain tumors and breast tumors, and in lymphoma and prostate cancer, are quite different. What these diseases have in common is that the division and migration of cells gets out of control.
Basically three types of events can happen in the earliest stages of turning normal cells into cancerous ones: The brakes can fail, the accelerator pedal can get stuck to the floor, and the mechanics can go out of business. When a combination of these things happens, all sorts of other problems arise, and a cell mass that may have been relatively benign, just growing into a lump where it first appeared, starts to metastasize. This means that some of the cancer cells begin to migrate to other parts of the body where they set up secondary tumors, greatly exacerbating the problems.
Framing this discussion of cancer biology in terms of brakes, accelerators, and repairs should help make it clear that the term “cancer gene” is something of a misnomer. It implies that there are genes for cancer, when the reality is that these genes are actually essential for growth and development but can cause cancer when something goes desperately wrong. At least one percent of our genes, and by some estimates more than ten percent, are primarily involved in controlling the timing and mechanics of cell division. This is literally hundreds if not thousands of genes.
Why so complex? Think for a second about what happens after conception. You start out life as a single cell and in the space of a few weeks become billions of cells in carefully orchestrated organs with distinct numbers of retinal, muscle, neuronal, skin, and blood cells. It should be obvious that there is plenty of opportunity for things to go wrong. The more so since the development of an animal is totally self-regulating: There is no template or design that a builder can refer to. Rather, the organism unfolds with only a billion years of experience as a guide to what works.
Coordination of the parts is achieved by thousands of different signals telling each cell what its neighbors are doing and what is going on in the rest of the body. Cells can divide only after the DNA has been replicated and scanned for errors, and when it is clear that various checkpoints have been cleared. A core set of twenty or so genes orchestrate cell division in all animals (and most of these are the same in plants as well), but more than ten times this number of genes provide the checks and balances that keep the process under control.
The brakes in this process are technically known as tumor suppressors. These are genes whose normal job is to stop one cell from dividing into two cells, either because the body is not ready for more cells, or because all is not right inside the mother cell that is getting ready to divide. When one of these genes is mutated so that a functional protein is no longer made inside the cell, it is as if the brake lining is gone, so cell division just keeps rolling along.
The most famous of the tumor suppressors are p53 and Rb. Most if not all tumor suppressor mutations are recessive, meaning that both copies of the gene must be nonfunctional for cancer to develop. Simply put, one copy is enough, so you can think of the second copy as a backup. In fact, most of our genes are like this. Rb provides an apparent exception, because in half of all cases of the eye cancer retinoblastoma, which affects about one in four million children and is responsible for three percent of all cancers up to the age of 15, the cancer seems to be hereditary. Worse than that, familial retinoblastoma is often transmitted in a dominant manner, and when it is observed, most often both eyes are affected by independent tumors. The major breast cancer susceptibility genes, BRCA1 and BRCA2, are like this as well.
The famous oncologist Alfred Knudson came up with an explanation for this phenomenon in 1971. Knudson’s hypothesis has since become the centerpiece of a general theory for the increased incidence of cancer with age. It supposes that it takes at least two “hits” for a cell to start to become cancerous. One mutation is not enough; both copies must be knocked out, and this is exceedingly unlikely to happen early in life. However, if an individual is born with one mutant copy in all of their cells, then it only takes a single second mutation for a cancer to arise. It is apparently almost inevitable that a second mutation occurs in children who inherit one bad copy of the Rb gene. When this happens, a tumor starts to develop in the eye, and if untreated by laser or some other type of microsurgery, leads to blindness or can spread to the brain.
By contrast, people who have unilateral, nonfamilial retinoblastoma are unlucky enough to get two mutations affecting Rb in their own lifetime. Tens of other tumor suppressor genes can suffer the same fate. It is even possible that two mutations in different tumor suppressors combine to initiate a cancer. As we get older, the chance of two hits occurring in one of our hundreds of millions of cells increases, and so does the likelihood of getting cancer. There is precious little we can do about this.
On the other side of the axle are the accelerators. These are genes whose normal role is to push cells through their natural cycle of growth and division. Technically known as proto-oncogenes, they typically pick up information from outside of the cell in the form of growth factors and send the signal into the part of the cell where other gene products orchestrate the replication of DNA and rearrangement of the furniture that is necessary for cells to divide.
Like the tumor suppressors, these genes are essential for life. The term proto-oncogene means that these genes are primed to become cancer-causing genes, or oncogenes. Oncogenes were first identified in chicken and mouse viruses, giving rise to an early theory that cancer is often caused by viruses. This is true in some circumstances, most notably cervical cancer, but more generally it turns out that the viruses were laboratory artifacts that had picked up activated forms of normal genes with names such as Ras, Src, and Jnk.
Oncogenes alone are capable of promoting cancer, but it would not be accurate to say they act alone. They are so crucial that a lot of redundancy is built into the system, so losing both copies of one of the genes can actually be tolerated quite well. We can engineer mice to have activated oncogenes in all of their cells, and such mice develop tumors predictably, but only a relatively small number of cells become cancerous. So other “hits” must be required here as well. Nevertheless, there is a key difference between oncogenes and tumor suppressors: The mutations that cause a proto-oncogene to become an oncogene are ones that, instead of destroying the gene, make it active all the time.
The fiendish protein products no longer respond to signals from outside the cell; they just do their thing anyway. It is as if the cruise control gets stuck in the on position, or the accelerator pedal is stuck to the floor. There are many more ways to break a gene than to activate it like this, so thankfully, activating mutations are rare enough that only a fraction of us get cancer. The other good thing about oncogenes is that they often result in an abnormally shaped protein that can be targeted by a very selective drug that stops the protein from being active.
The third wheel of cancer genetics is the team of mechanics that repair DNA. If the DNA is broken, then so too eventually will be the instructions for making the brakes and accelerators, and many other things can also go wrong. When the major gene for familial colon cancer was identified a few years ago, DCC1 (Deleted in Colon Cancer 1) turned out to encode a DNA repair enzyme.
Throughout your life, bad things happen to your DNA. Ultraviolet radiation in sunlight causes pairs of adjacent Ts to link together, and if these are not fixed, the code will change next time the cell divides. Similarly, all sorts of toxins that we eat, chemicals in tobacco smoke, and other carcinogens get into the nooks and crannies of the double helix and break it or otherwise chemically modify it. Having broken repair enzymes is not a good thing. Why the colon and breast should be particularly susceptible to this kind of problem is anyone’s guess, but in all likelihood DNA repair is eventually damaged in most advanced stage cancers. Unfortunately, no drugs can take the place of the broken enzymes, so cancer biologists have to try to alleviate the consequences of DCC and BRCA, rather than fix the root problem.
I do not want to leave the impression that mutation of any of these three major components is sufficient for cancer. Current thinking is that such mutations are necessary to start a long process of tumor progression. Slowly at first, but gradually building and eventually snowballing, a mature tumor bears little resemblance to the normal cells in our bodies, as it comes to operate on its own terms. By the time a tumor is actually observed, it is vastly different from the initial cell that managed to escape the shackles imposed on it by the rest of the body. Large chunks of the chromosomes may be lost or duplicated, and tens or hundreds of genes might have picked up mutations.
An intense classical Darwinian struggle goes on inside the tumor. Any new mutation that improves the rate at which the cancer cells propagate is likely to result in that cell outgrowing the others. If you think about it, the nucleus of a cancer cell is the ultimate in selfish DNA. That one cell that starts a tumor may in the course of ten years have more descendants than the first germ cells that founded modern humans 100,000 years ago. In the language of Richard Dawkins, tumor cells are the ultimate replicators. If the sole purpose of existence were to reproduce, you’d be well advised to become a cancer cell.
However, the strategy is ultimately self-defeating. Organisms have evolved complex mechanisms to suppress cancer cells because short-term reproduction is not in the best interests of long-term survival. The community of cells is a nonselfish one in which the various parts work together in harmony. This is a metaphor for life that I find far more enticing and accurate than the nature red in tooth and claw metaphor that so often characterizes popular portrayal of evolution.
Familial Breast Cancer
Only about ten percent of breast cancer runs in families, in the sense that sisters and daughters of an affected woman have elevated risk compared with the general population. Of this fraction, one-fifth can be attributed to two genes, BRCA1 and BRCA2. Women who inherit one bad copy of either of these genes have a lifetime risk of ovarian or breast cancer exceeding 85 percent: Each gene thus accounts for about 1 in every 100 cases of the disease. That is worth worrying about if you are in an affected family, but the flip side of this is that 97 percent of breast cancer has no known genetic basis.
Here and there, studies have by now implicated mutations in at least ten different genes in promoting specific cases of familial breast cancer. Literally thousands of known mutations are in these genes, but a handful of relatively common ones account for most of the disease that runs in families. For example, a not particularly uncommon deletion of a single nucleotide in CHEK2 is pernicious but not as bad as the BRCAs, only increasing risk perhaps twofold. If you carry this mutation, the odds are still pretty good that you’ll be all right. The other mutations are so rare that they are found in only a handful of individuals. Many of the proteins that these genes encode work together as a mechanical complex that prevents something called genome instability. If the cell’s mechanics don’t work appropriately, then after a while the chromosomes basically either fall apart or divide inappropriately, leading either to abnormal growth or cancer.
Our best explanation for the relatively high incidence of these breast cancer susceptibility alleles in the human population, somewhere around two percent of all people, is genetic drift. Just like every other gene in the genome, upwards of 1 in 100,000 people are born with a new mutation in BRCA1 or BRCA2 or any of the other yet-to-be-identified tumor suppressors in the group. These individuals have the same predisposition to cancer as people who inherit a mutation from their parents instead of contracting their own. Given the late onset of disease, there is no reason why most of these people won’t have just as large families and normal lives as everyone else. Consequently, the mutations can hang around in the gene pool without doing too much harm, and some of them can drift to more common frequencies.
Nature does not eliminate all of them, because it has much more severe problems to deal with, ones that act earlier in life and negatively impact more lives. Until recent times most breast cancer susceptibility mutations had a negligible impact on public health. Now that women live longer and have greater lifetime estrogen exposure, the mutations are contributing to the increased frequency of breast cancer. As small groups of people settled new lands, if a few of the founding men or women carried a susceptibility allele, it would easily have reached the kinds of frequencies that we see in, for example, Ashkenazi Jews for BRCA1. This is just a normal consequence of population genetics, not at all a unique property of cancer genes or Jewish habits.
Growth Factors and the Risk to Populations
Turning now to the vast majority of cases where breast cancer does not run in families, we can still ask whether genes might be involved. Groups all over the world have been tackling this question from different angles for a dozen years. For the most part they have been taking educated guesses and following up suggestive leads. In 2005, a consortium of 20 of these groups decided to pool their resources and look to see whether there were any consistent results in their combined set of more than 30,000 cases of breast cancer, admittedly mostly in Caucasian women.
The outcome was somewhat humbling. Just two genes out of the nine best guesses showed a consistent association with risk of cancer. The most convincing of these is a variant of the gene CASP8, which provides a modest protection against breast cancer for about a quarter of all women. The gene is involved in getting cells to commit suicide when damage to the DNA is sensed. It is the only case we know of to date where the protective variant is the less common one, where most women are at greater risk of cancer because they have the more common flavor of genetic variation.
The other gene encodes an important growth factor known as TGFβ, short for Transforming Growth Factor Beta. This gene is required for breast development in the first place. It is thought on the one hand to counteract the early development of tumors, but on the other to promote their aggressive growth after they are established. In this case, the “bad” version of the gene increases the risk of breast cancer by around seven percent in carriers and 17 percent in women with two bad copies. It is the less common allele in the population, but not by much, and about half of all women carry the risk factor.
About the same time, a group based in Cambridge, England, took a different approach. They decided to look at a lot more genes in their cohort of 4,400 patients and 4,400 age-matched cancer-free women. No single gene emerged as a significant risk factor. However, they did find a trend implicating two sets of genes as if they were gangs of teenagers looking for trouble in the neighborhood. It is tough to pin the crime on any one, but collectively they carry a smoking gun.
One group is involved in regulation of when and how often cells divide. It is not hard to imagine variation in such genes contributing somehow to cancer risk. The other group is involved in steroid hormone metabolism. This is interesting, because the leader of the gang is ESR1, the estrogen receptor. Recall that the combination of earlier menarche (the first menstrual period) and later menopause, both leading to altered estrogen levels in modern women, is now thought to be the leading candidate for the increased incidence of disease over the past several decades. If there are genetic variants that reduce estrogen exposure, it stands to reason that these would tend to be protective against breast cancer.
Subsequently, by 2007, the large consortium had a handle on another half dozen candidates after scanning the whole genome. Several of these don’t immediately make a lot of sense (one is a heck of a long way from any known genes), but three of them also implicate variation in the transfer of hormonal signals inside cells.
Much the strongest case is for FGFR2, a receptor for Fibroblast Growth Factor, which as the name implies is a protein that normally encourages skin cells to grow. In some breast cancers, FGFR2 is amplified in the genome, and there is evidence that different shapes of the protein produced by splicing together different bits of the gene, vary in their effectiveness. It now looks as though two-fifths of all women have some changes in a part of the gene that affects how it is expressed—either how much is made or how it is stitched together—and that these women are more likely to get breast cancer than the majority of women. Of all the women who will have breast cancer at some point in their life, almost one half will carry the “bad” allele of FGFR2, and for one quarter both alleles will be of the bad variety.
A large American study has confirmed that this is the case also for postmenopausal women who show no family history of the disease. This one gene, then, accounts for as much as one-seventh of the total genetic risk for breast cancer in the general population. That sounds like a lot, but keep in mind that most of the disease is sporadic, and not caused by genetic variation. In other words, there is no reason for anyone to rush out and get tested. FGFR2 is simply not predictive on its own, and the great majority of carriers will never get breast cancer. In fact, putting together all the evidence from the half dozen new genes explains only another five percent, in addition to the ten percent for the BRCA genes, of the increased risk even in familial breast cancer.
It is highly unlikely that any more genes remain to be discovered that have effects of the same magnitude. It is much more likely that hundreds of susceptibility factors are sitting around in the genome, each with extremely modest effects or only to be found in relatively few people. Every woman probably has some of them, but it is the total constellation that elevates or depresses her risk of cancer—well, that plus lifestyle factors and raw chance.
Pharmacogenetics and Breast Cancer
Many physicians would argue that we ought to be more interested in finding the genes that mediate how a person responds to cancer therapy than in finding the genes that cause cancer in the first place. Traditional cancer treatments were like taking a sledgehammer to dividing cells. Radiation breaks the DNA into fragments that the cells have a hard time putting back together as they are dividing, while the older chemotherapeutics generally inhibit the replication of DNA. These treatments cause hair loss, nausea, and other side effects because certain types of cells in the body are always dividing as a normal part of life, and these are affected by the nonspecific cancer treatments.
The new drugs by contrast are designed to target just the cancer cells. They do things such as interfering with the receptor proteins on the cell surface, messing up the communication pathways specifically inside cancer cells, enticing them to commit suicide, or disrupting the blood flow to growing tumors. In many cases, it is not exactly clear how the drugs work, and some really effective drugs fail in clinical application because of “off-target” effects elsewhere in the body.
Just how far genomic medicine has and has not come in the few years since the completion of the first draft human genome sequence is shown by title of an Act introduced to the U.S. Senate by Barack Obama. The Genomics and Personalized Medicine Act of 2006 (S-3822) proposed several initiatives, and a large amount of money, to accelerate the translation of genome science into clinical practices. It is foreseen that these will eventually be simultaneously tailored to the unique genetics of each patient and sensitive to the racial and environmental circumstances of the individual.
Upwards of 100,000 hospital patients lose their lives each year as a consequence of adverse drug responses. For example, 85 percent of the cases of childhood acute lymphoblastic leukemia can be treated with the drug 6-MP. Unfortunately, one in ten children carries a variant form of the TMPT gene, and as a consequence they are unable to metabolize the drug. If physicians know this, they can reduce the dosage and eliminate the adverse response, helping thousands of children a year. Who wouldn’t want to see the widespread application of such personalized medicine?
Contemporary cancer therapy is already tailored to molecular attributes of biopsy samples. FGFR2 is just one of the many receptors that provide hints about what the cancer cells are responding to inside a person’s body. Two of the other most important biomarkers are HER2 and ER, components of the receptors for Epidermal Growth Factor and estrogen, respectively.
A quarter of all advanced breast cancers make too much HER2, and this is associated with increased recurrence rates and hence mortality. In one of the early success stories for medical biotechnology, Genentech set out to specifically inhibit HER2 activity by making a molecule that binds to and inactivates the receptor. The drug, trastuzumab, trademarked as Herceptin, is actually a modified antibody, just like the antibodies that your body normally uses to fight infections.
A course of treatment costs in excess of $70,000, so health care providers have been reluctant to approve its use for treatment of early stage cancers. Increasing evidence suggests though that early intervention can be highly effective, potentially saving not just lives, but hundreds of millions of dollars a year in care for terminally ill patients. For this reason, the pharmaceutical industry is extremely active in developing new inhibitors of HER2 and other receptors like it that are implicated in numerous cancers. GSK’s Tykerb, AstraZeneca’s Zactima, Novartis’s Gleevec, and Genentech’s Tarceva are just a few examples of such so-called tyrosine kinase inhibitors to watch for over the coming decade.
The chemotherapeutic drug of choice for combating estrogen responsive cancers has long been tamoxifen. This compound was actually first developed in the 1960s as a potential contraceptive pill. Effective for that purpose in rats, it turned out to stimulate ovulation in human women, not exactly a desirable property of a contraceptive. Further studies revealed it to be an effective antagonist of estrogen in breast tissue, and consequently an excellent drug for inhibiting the ability of the hormone to stimulate growth of Estrogen Receptor positive cancer cells.
A new generation of Selective Estrogen Receptor Modifiers (SERMs) is being introduced that get around some of the problems with tamoxifen, which is now also known to increase the likelihood of development of uterine and endometrial cancer. Eli Lilly has developed a similar drug known as raloxifene and marketed as Evista, which appears to be as effective in reducing recurrence of breast cancer, without the side effects. This drug is also unaffected by a common enzyme type, CYP2D6, that digests tamoxifen and reduces its effectiveness for some patients.
Down the road, genomics experts see a day when profiling cancers with a new technology known as microarray analysis will allow physicians to tailor particular drug regimens according to the entire molecular signature of the cancer. The idea is that the profile of hundreds of genes is likely to be more predictive than just the two or three that are currently examined. Hundreds of millions of dollars are being invested in this possibility, but it remains to be seen whether the technology will deliver on its promise. Currently the approach has limited approval for use with low-grade cancers where treatments are ever improving anyway.
This new approach also holds promise for guiding supplementary treatments when cancers evolve resistance to drugs such as Herceptin. Such is the competition among cells that when humans try to conquer their uncontrolled growth with drugs, the cells escalate the arms race by accumulating mutations that thumb their noses at the treatment. There are as many ways this can happen, as there are signaling pathways inside cells. Unlike normal cells, cancerous ones don’t care to behave as they should; they just want to survive and divide. By looking at all the genes at once, clinicians hope to be able to target just those processes that have gone particularly sour.
Why Do Genes Give us Cancer?
Why hasn’t natural selection ensured that the protective versions of all the genes associated with cancer development or progression are the predominant type in the human population? The answer to this question is quite possibly a good example of the disequilibrium between our modern genetic makeup and what might have been the ideal human genetic condition throughout our history as a species.
Female reproduction is one of the traits that evolved most rapidly in humans relative to other primates. Hormonally regulated processes such as the timing and cycling of menstruation and preparation for breast feeding changed greatly a few hundred thousand years ago. This almost certainly involved selection on genes involved in hormone production over a period of thousands of generations.
Advocates of fundamentalist Darwinian medicine would probably make the argument that breast cancer is better regarded as an example of genomic conflict. They would argue that since all organisms are attempting to maximize the number of offspring they have, mutations that cause estrogen to be produced earlier in girls will tend to advance menarche and hence lead to earlier pregnancy, increasing the number of children they have. However, since as adults they are more likely to have breast cancer, there will be an opposing force of negative selection, setting up a trade-off that leads to the balance that ensures that puberty comes in the midteens.
What is wrong with this type of argument? Let’s start by recognizing that earlier childbirth does not necessarily translate into having more children over a lifetime, and even if it does, it does not necessarily mean that the children will be more “fit.” Birth weight is a vital indicator of child mortality and health, and is a function of maternal health. Menarche generally occurs only after a girl reaches a total body fat level of 17 percent, and the regularity of menses is also a function of growth and nutrition. Nobody knows what the relationship between early motherhood and long-term fitness may have been during human evolution.
Next we must recognize that breast cancer is predominantly a postmenopausal disease, meaning that it affects women after childbearing age and hence is not selected against with respect to having children. True, it is not advantageous for a child to have her mother die young. We also know that given the fullness of time, nature can sift through genetic differences that have an impact of just a fraction of a percent on childbearing. So I am not saying that there is no selection against alleles that promote cancer late in life. But I am saying that it takes a lot more careful empirical observation and mathematical reasoning to establish the argument than just to make it casually.
Was the incidence of breast cancer high enough to trade-off against any possible benefits of early pregnancy? It is almost impossible to know and seems unlikely. Any trade-off argument is a gross oversimplification. Estrogen regulates hundreds of coordinated processes; timing of menarche and menopause are changing against a background of dramatic remodeling of reproductive strategies and of primate lifespan, not to mention mortality and health risks. A few hundred thousand years is a very short time to expect the genome to come to some sort of equilibrium.
What we can be confident about is that there is genetic variation affecting estrogen production, that this variation has been under selection throughout human history, and that any connection to breast cancer liability is likely to be incidental. Now throw in all the changes that modern society has wrought—excellent childhood nutrition, cultural taboos against teenage pregnancy, the obesity epidemic, stresses on nuclear families and social relationships, longevity—and whatever effect that variation had in the past is turned upside down. Don’t expect a new equilibrium any time soon, and don’t expect the genetic risk factors to go away either.
A couple of naïve but legitimate questions remain that deserve to be asked about why cancer is so prevalent, accounting for as much as a fifth of human mortality, if this natural selection thing is supposed to be so efficient. Why would there be cancer genes at all, and why hasn’t the evolutionary process done something about them? I do not have a quick sound-bite answer, other than to reiterate that cell division is so complex that there is ample scope for it to go wrong, and that the high incidence of cancer is really a modern phenomenon. Let’s recap the salient facts from this chapter that might help us to understand this better.
First, the terminology “cancer gene” is at best misleading and definitely inappropriate. It implies that there are for some reason genes whose job it is to cause cancer, just like there are viruses and bacteria that seem to exist solely to cause misery. The reality is that hundreds of genes that are perfectly good and vital citizens of the genome unfortunately mutate into forms that contribute to cancer. The most insidious mutations affect genes whose function it is to protect the genome by repairing the DNA: When these stop working, the genome starts to fall apart, and cells lose control of their place in the organism.
Every single human carries mutations in several of these genes, but since a lot of redundancy is built into the control of cell division, it does not much matter. At least, not until new mutations build up in our cells during the course of life, knocking out these failsafe mechanisms. This is why chance plays the major role in determining who will get cancer: It is just a stochastic matter of who is unlucky enough to find themselves with a bad combination of mutations that the body cannot eliminate.
Second, we shouldn’t blame the genes for cancer: By far the greatest threat comes from environmental factors. Smoking or hanging out in smoky bars, not eating your greens, tanning in the midday sun, and the combination of early puberty with delayed pregnancy, are all to blame. These are things we can do something about, though reality usually steps in the way, and most of us make a Faustian pact to trade a little extra cancer risk for the pleasures of social engagement, healthy looks, or an independent career. The one thing we cannot do anything about, though, is the biggest environmental factor of all, and that is growing old.
Cancer is fundamentally a product of disequilibrium between our genome and our culture. All of a sudden, in the space of a couple of generations, humans are living 20 years longer than ever before. Cryptic genetic susceptibility factors that have only a miniscule effect up to the age of 50, too small an effect for natural selection to do anything about, are now uncovered. These variants account for maybe a quarter of all mortality in old age, but they just have not played a significant role in human history hitherto.
Third, those cases where we can blame specific genes, account for only a small proportion even of cancer that seems to run in families. BRCA1 and BRCA2 are the two best-known susceptibility genes. If you are a woman who inherits a mutation in one of these two genes, you have a high lifetime probability of having breast cancer. Literally hundreds of mutations of this type are in the human gene pool, most very rare, but some at a frequency as high as a few percent in particular populations. Yet, the mutations only account for one-tenth of familial breast cancer, which in turn is one-tenth of all breast cancer. Geneticists are just now uncovering a few other genes that harbor mutations that also contribute, but the bottom line is that we just do not know what genes account for the majority of breast or any other type of cancer.
In fact, we don’t really have a good model for how they act either. Knudson’s two-hit hypothesis has served pretty well as a starting point. The idea is that you need at least two mutations to initiate cancer. If you inherit one from your parents, you are off to a bad start, because you only need one more during your life. Since that first mutation is insufficient to cause cancer, it can hang around in the gene pool, ever so slightly increasing the incidence of cancer and contributing to its tendency to run in families. Presumably there are hundreds of genes harboring such mutations and hundreds of different mutations in each of these genes, each of which increases cancer susceptibility a fraction of a percent. Eventually we will find many if not most of these, but it is doubtful it will do us much good.
Though not discussed here, a lot of cancer susceptibility has more to do with what happens in the progression from initial lesion to mature tumor, than in the initial appearance of cancer. The potential of cancer cells to metastasize (start migrating around the body), their ability to vascularize (attract blood vessels to support malignancy), and the capacity of the immune system to detect and deal with an early stage cancer are all affected by our genes. Our psychological and nutritional status can play an enormous role here as well.
Putting all this together, the inescapable conclusion is that we are dealing with an immensely complex foe. The media, naturally, likes to report from time to time that scientists have identified a new gene for cancer. Our response is to assume that this is something like a gene for blue eyes or male-pattern baldness: If you get it from your parents, you are going to get cancer, and the reason why we cannot yet predict cancer is because we haven’t found the genes yet. The truth is otherwise.