Angelina Jolie made the headlines with her just-in-case mastectomy, but was her genetic history a loaded gun, as her doctors warned her?
Actress Angelina Jolie won plaudits around the world after making public in May her decision to have a double mastectomy as a preemptive strike against what doctors told her was a whopping 87 per cent risk of developing breast cancer and a 50 per cent chance of developing ovarian cancer. Jolie carries a mutation of her BRCA1 DNA-repairing gene and has a history of breast cancer in the family; her mother Marcheline Bertrand died at age 56 of ovarian cancer after a decade-long fight against the disease, and her mother's younger sister recently died of breast cancer.
Jolie, who regularly uses her fame for public good, said she chose not to keep her story private in the hopes that other women who may be living under the shadow of cancer "will be able to get gene-tested" and know about their "strong options" should they turn up a bad genetic turn of the dice.
After her public announcement, many other women came forward to talk about their just-in-case mastectomies, and the stock price of Myriad Genetics, which patented the BRCA1 and BRCA2 gene tests, rocketed upward by 3 per cent.
While Jolie's decision to tell the truth about her own situation was brave and extraordinarily well-intended, how much of the truth was she herself given about her condition and whether genetic history is indeed an automatic death sentence? Here's what doctors may not have told her.
Most breast cancer develops in women without a family history of the disease.
Although women with a family history of breast cancer are assumed to be at greater risk of developing the condition, to determine how much this risk is influenced by particular familial patterns of breast cancer, the Imperial Cancer Research Fund's Cancer Epidemiology Unit in Oxford examined the health records of the mothers, sisters and daughters of more than 160,000 women and discovered that the vast majority of women who get cancer (eight out of every nine) don't have a family history of the disease-and even when they do, most will never develop cancer.1
Most women with a family history of breast cancer will never get the disease.That same large-scale Oxford study found that four out of five women who have a mother and a sister with breast cancer will never develop breast cancer, and 12 out of 13 will not die from the disease. The risk does increase with the number of close relatives who have the disease, but the risk is far less than described to Jolie. For women with one close relative with breast cancer, the lifetime risk is 8 per cent, which increases to just 13.3 per cent for those like Angelina Jolie, with two close relatives who had the disease.1Mutations in the BRCA1 and BRCA2 genes are rare, accounting for a tiny fraction of all breast cancers in the UK and less than one-fifth of the familial risk of breast cancer.2
There is no solid evidence that just-in-case double mastectomy increases survival.
The Cochrane Breast Cancer Group recently carried out one of the largest reviews of just-in-case mastectomy, examining 39 studies involving some 7,000 women who'd had prophylactic (just-in-case) double mastectomies, some on two healthy breasts and others with cancer in one breast who chose to remove the other, healthy breast as a preventative measure. Although some of the studies showed that women who'd removed two healthy breasts lowered their risk, there were so many problems with the designs of the studies that no firm conclusions could be drawn, said the authors. For women with cancer who'd removed the other healthy breast, the only well-controlled study showed no overall survival advantage. Furthermore, up to 49 per cent of all the women suffered complications requiring repeat surgery. The authors cautioned that many women who opt for this procedure "may overestimate their breast cancer risk".3
An environmental 'trigger' that causes cancer seems to be more important than family history.
Several epidemiologists at the University of Rochester Medical Center in Rochester, New York, examined data from the American Women's Health Initiative (WHI), one of the largest studies to follow women using hormone replacement therapy (HRT) and which was abruptly halted, along with the use of HRT, when it became apparent after five years that the 16,000 participants taking hormones were at increased risks of developing breast cancer, ovarian cancer, stroke and heart disease.4
When the Rochester scientists combed through the details of the women taking part in the WHI study who had got breast cancer, they naturally assumed they would find a higher incidence of cancer among those who had a family history of the disease.
However, the evidence showed a similar incidence of cancer among those taking HRT whether or not they had breast cancer in their genetic history. The particulars of a woman's genetic makeup and family history of cancer appeared to have nothing to do with it.5In this case, the environmental stressor-artificial hormones taken regularly-was the main trigger.
Environmental stressors at certain key points in life may have more of an impact on the future health of offspring than genes.
The most powerful risk factor passed on from mother to daughter may not be her genes, but what she took or was exposed to during pregnancy. Several studies show that feeding animals high-fat diets or exposing them to oestrogens during pregnancy increases the risk of breast cancer among the female offspring.6The researchers at Georgetown University also concluded that dietary programming during critical times in a daughter's life (as a foetus and then during puberty) has the most influence on the expression of genes like BRCA1.7
Our own exposure to epigenetic (environmental) factors may be the strongest determinant of whether or not we will develop cancer.
The conventional view is that our genetic destiny is fixed and inherent in our DNA, the body's central blueprint, which operates through a straightforward mechanistic process of selectively turning on and off certain genes, the steps on the spiral ladder of the double helix. These nucleotides, or genetic instructions, make copies of themselves as messenger ribonucleic acid (mRNA) molecules, which choose from an alphabet of amino acids the genetic 'words' to create the body's approximately 150,000 specific proteins that carry out its myriad functions.
Cellular informational commands were believed to flow in a single direction-from DNA and mRNA to the selected combinations of amino acids and assemblage of proteins. Until recently, scientists maintained that gene activity was a hermetic process that took place independently of the environment.
As new research decisively demonstrates, genes-far from being the central controller-exist purely as potentials to be activated or not by signals outside our body, much as a piano is silent until someone sits down to play it.
An environmental signal of some sort alerts the body that a particular protein product is needed, and it is the outside environmental signal that activates that particular genetic expression. Genes get turned on, turned off or modified by our environment: what we eat, who we surround ourselves with, and how we lead our lives.
In fact, new evidence shows that even a faulty BCRA1 gene, as Jolie has, may require epigenetic modification, or 'silencing' and deletion, before it can progress to cancer.8
All of the recent research on epigenetics casts a long shadow on the idea fed to Angelina Jolie and many other women that illness is simply a case of having 'good' or 'bad' genes by showing that the on-off switches for genetic expression are more likely to be controlled by environmental triggers. Diet, a strong social network and community ties, purposeful work, mental stimulation, and an environment free of toxins and pollution may be far more important than the genes you were born with in determining whether you get cancer.
How the cancer trigger works
Cytoplasm, the blob of jelly that makes up every cell in your body, is encased in a semi-permeable cell membrane, a triple layer of fat-like molecules containing a variety of protein molecules that act like little revolving doors for other molecules to enter or exit the cell. Whether or not a molecule gets through the cell membrane depends entirely on these gatekeeper proteins, which are called receptors because they function like antennae, picking up external signals from other molecules and, in turn, signaling to effector proteins to modify the cell's behaviour.
Every cell's membrane contains hundreds of thousands of these protein receptor switches, which possess the ability to regulate cellular function by switching certain genes on or off. But what prompts the turn of the switch is an environmental signal-from the air, water and food we consume, the toxins we're exposed to, even the people we surround ourselves with. This in turn affects the methylation of the DNA double helix, which is exquisitely sensitive to the environment, particularly in the early stages of life. During this process, the methyl group, a quartet of atoms, attaches to a specific gene and sends it a message to silence it, reduce its expression or in some way alter its function.
New evidence reveals that this configuration, often termed the 'epigenome', has the potential to serve as an interface between the outside and inside of the body by acting as the gene's interpreter of environmental signals. This signaling takes place not within but on top of the gene and does not alter the genetic sequence or interfere in any way with the letters of the four-unit genetic code.1
Epigenetic changes and the ultimate expression or silencing of a gene arise as a result of environmental stressors. Diet, the quality of air and water, the emotional climate within your family, the state of your relationships, your sense of fulfillment in life-the sum total of how you live your life and also how your ancestors lived theirs-have the greatest effect on how, even whether or not, your genes are expressed.
1.Lipton B. The Biology of Belief. Carlsbad, CA: Hay House, 2008
One aspect of Jolie's case never discussed is the two risk factors she will now be exposed to in the process of attempting to lower her genetic risk of cancer,factors that increase her risk of getting cancer far more than her so-called 'faulty' genes might have.
Breast implants have been linked to a rare type of breast cancer known as 'anaplastic large-cell lymphoma' (ALCL), a form of non-Hodgkin lymphoma, increasing risk of contracting the disease by 18 times.9
If Jolie chooses to have her ovaries removed and starts taking HRT, the latest evidence from the WHI study confirms that women who take the standard oestrogen/progestin HRT are more likely to develop breast cancer and die from the disease. In fact, they were 60 per cent more likely to die from any cause.10Epigenetics and cancer
At the forefront of research into the environmental influences of cancer is a team at McGill University in Montreal led by Moshe Szyf, an Israeli-born professor of pharmacology and therapeutics. Szyf discovered that a major hallmark of cancer is an aberration in methylation patterns (that is, epigenetic modifications made to the gene after it replicates), so that the genes needed for rapid cell growth, cellular invasion and metastasis aren't kept in check .1
Szyf believes the problem has to do with both too much and too little: too much methylation in breast cancer, for instance, can silence the genes needed to regulate cell growth, and too little tends to activate genes involved in rapid metastasis (spreading).2
Szyf has also demonstrated that epigenetic influences don't only occur early in life. In a series of studies in animals, he showed that numerous kinds of stress responses deliberately programmed into a variety of animals by one set of conditions early in life could be deprogrammed out of the organism by changing conditions later in life. For example, Szyf was able to reverse brain abnormalities in baby rats caused by unhealthy mothering by handing the rat pups to foster mothers who treated them normally. This suggests that some epigenetic conditions may be fluid-reversible in adulthood as well as in infancy.3
1. Cancer Lett, 2004; 211: 133-43
2. Biochem Pharmacol, 2007; 73: 1297-307
3. Proc Natl Acad Sci U S A, 2006; 103: 3480-5
The (agouti) mouse that roared
One of the earliest studies to reveal the power of epigenetics to turn genes on or off was the now famous study of agouti mice carried out by Randy Jirtle, professor of oncology at Duke University, and his graduate student Rob Waterland.
Jirtle and Waterland wished to test whether changing certain external conditions could turn off the expression of genes programmed for disease and so reverse genetic destiny.
Jirtle and Waterland decided to carry out their study on agouti mice, which possess a genetic defect in their agouti viable yellow (Avy) gene, which encodes the signaling molecule for hair colour, ordering the hair follicles to produce a yellow coat rather than the customary brown. Besides being golden-coloured, these mice are often hugely obese with a tendency to develop diabetes and cancer.
Waterland and Jirtle bred 10 litters each of test agouti mice and controls. Half the female mice were fed extra B vitamins before they became pregnant, during pregnancy and also during lactation, while the other half received only the usual mouse chow.
After isolating the genetic codes of each animal, Waterland found an obvious difference in one aspect of the code in mice whose mothers had been supplemented.
The genetic code for proteins comes in four versions, designated by science as A, C, G and T (referring to nucleotide bases adenine, cytosine, guanine and thymine). In a huge proportion of the offspring of mice given the B vitamins, C had been transformed into T. The B-vitamin supplements in a sense had turned on a different gene.
Changes in gene expression were also physically obvious. A larger percentage of the offspring of mothers that had received the enriched diet were a normal brown in colour and also less susceptible to adult degenerative diseases like diabetes and cancer. Unlike their mothers, this generation of mice lived out a normal lifespan.1
The dietary supplements had dramatically overridden the offspring's genetic destiny by turning off the agouti gene's expression. With their little batch of mice, Jirtle and Waterland had proven that a few simple environmental modifications in the life of a living thing could take charge of its genetic destiny.
1. Mol Cell Biol, 2003; 23: 5293-300
1 Lancet, 2001; 358: 1389-99
2 Br J Cancer, 2000; 83: 1301-8
3 Cochrane Database Syst Rev, 2010; 11: CD002748
4 JAMA, 2002; 288: 321-33
5 Epidemiology, 2009; 20: 752-6
6 Nat Commun, 2012; 3: 1053
7 Ann N Y Acad Sci, 2006; 1089: 14-35
8 Breast Cancer Res, 2006; 8: R38
9 JAMA, 2008; 300: 2030-5
10 J Natl Cancer Inst, 2013; 105: 526-35