[Originally posted on Occam’s Corner at Guardian Science, in February 2014]
In the 2000 M Night Shyamalan film Unbreakable, Samuel L Jackson’s character – a man born with a severe form of brittle bone disease – asks Bruce Willis’s character, ‘if there is someone like me in the world, and I am at one end of the spectrum, couldn’t there be someone else, the opposite of me at the other end? Someone who doesn’t get sick, who doesn’t get hurt like the rest of us?’ Some cancer researchers are trying to answer the same question; however, in real life, it’s just not that easy to unmask a superhero
In June 2013, I described how sequencing the highly abnormal genomes of cancer cells can identify some of the mutations that drive the progress of the disease (and how that’s only the beginning of the story). In the discussion that ensued, reader BlueSky3 commented:
Hope more likely rests in examining the control systems/defence mechanisms of those carrying a hereditary cancer fault which has perhaps persisted in evolutionary time. Not all mutation carriers succumb. Why not?
This comment was so interesting that it’s been percolating at the back of my brain for months. We know that women who inherit a faulty copy of the BRCA1 or BRCA2 gene have a highly elevated risk of developing breast or ovarian cancer – but cancer is not an inevitability. We also know that smokers have a highly elevated risk of developing lung, throat, or oral cancer – but some of them don’t. Why?
The answer lies in the complexity of cancer. The first mutation that starts the first abnormal cell down its path to malignancy can be caused by any number of factors: genetic predisposition, radiation, chemical agents, viruses. Similarly, any number of factors can influence the direction the disease travels thereafter. The first mutated cell has to escape everything the body can throw at it – DNA repair, the shutdown of cell division, programmed cell death, the immune system – before it can become truly dangerous. This complexity creates a number of possible points of intervention. Many, especially those related to the health of the immune system, are at least partially related to lifestyle factors, but in this article I’m going to focus on natural-born superheroes only – that is, those who inherit genetic factors that protect them from cancer.
The suggestion to study people with known cancer predisposition mutations who don’t go on to develop cancer is a great one, but not an easy one. If someone is unaware they have such a mutation, and they remain healthy, doctors and researchers have no way to identify them as a subject of interest. Additionally, many people who do know they have such a mutation can now take preventive measures (such as Angelina Jolie’s recent pre-emptive double mastectomy upon learning her BRCA gene mutation status), and we have no way of knowing whether they would have gone on to develop cancer if these measures had not been taken. All this adds up to a very small sample size to study, which makes the identification of subtle genetic correlations extremely difficult. It is possible, however, to search for “superhero” genes among the much larger general population, and to relate some of the findings back to more specialised populations such as those with inherited mutations in BRCA and other cancer susceptibility genes.
Many years ago, I attended a seminar by local researcher Michael Hayden about using very rare genetic disorders on one end of a spectrum to find new ways to fight very common disorders at the other end of the same spectrum. For instance, Hayden learned of a family with an inherited inability to feel pain, and was able to identify the faulty protein responsible; his lab recently published the results of a preliminary trial of a drug that targets the same protein in people without the disorder, and that may represent an entirely new class of painkillers.)
Unfortunately, finding people with genetic protection from cancer isn’t this straightforward. A person with no ability to feel pain will come to the attention of the medical profession early in life, when they walk for a week on a broken bone or show some other outward sign of their mutation. However, someone with an unusual degree of genetic protection from cancer is unlikely to present in the same way, making it harder to identify the relevant gene variants and to extrapolate from this knowledge to find a way to help prevent cancer in others.
Scientists are a resourceful bunch, though, and we’re starting to make progress despite these limitations. One approach is to look for protective gene variants in the general population, by comparing the gene sequences of people with cancer to those of healthy controls of comparable age and with similar risk factors. For example, in 2004 Angela Cox’s group at the University of Sheffield looked for correlations between breast cancer and the sequences of genes involved in programmed cell death. (This process, also known as apoptosis, is one of the body’s defence mechanisms that a cancer cell must evade if it is to go on to form a tumour. Apoptosis can be triggered by a number of different signalling pathways, each with multiple components; see the diagram for part of the picture.)
Cox’s team found that women who’d inherited a variant called D302H in the apoptosis-related CASP8 gene were less likely to develop breast cancer. This variant has since been shown to correlate with a reduced risk of prostate and other cancers, and in 2010 the Group for Assessment of Hereditary Cancer of Valencia Community reported that “CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers” – making its carriers not unbreakable, but definitely less fragile than the rest of us.
Like so many others, recent technology advances mean that this field of research is now dominated by large-scale whole-genome studies. In 2013, a major European cancer genetics consortium called COGS(Collaborative Oncological Gene-environment Study) published a series of papers describing the results of a massive genome-wide association study of 100,000 cancer patients and 100,000 healthy controls. The study was designed to identify genetic variants that affect the risk of developing hormonally mediated (ie breast, ovarian and prostate) cancers. As expected, most genetic variants were found to increase the risk of cancer, but a few protective variants were also identified. For example, a variant in a component of the telomerase enzyme, which repairs the protective cap structures at the end of chromosomes, correlated with longer caps and reduced risk of some forms of breast cancer, including BRCA-related breast cancer.
The power of whole genome sequencing is also being applied to the study of people of advanced age who’ve avoided the most common causes of death, including cancer. There are a number of “super-ager” studies of this kind under way, including one at my organisation (I’m not involved with the project in any way, but I hear about it in meetings and in conversations at the pub after work). Dr Angela Brooks-Wilson leads the study, which involves sequencing the genomes of people aged 85 or older who are in good health, and who’ve never been diagnosed with cancer, heart disease, stroke, pulmonary disease, diabetes, or Alzheimer’s disease. It’s early days still, but hopes are high.
Back in June, reader BlueSky3 continued:
We are spending millions on dissecting the ‘cancer genome’ in minute detail and on genome wide association studies, shame a bit of the research money cannot be diverted to genetically dissecting the differences between mutation carriers living into their nineties and their less fortunate relatives who succumb to cancer in their thirties
I hope this article has demonstrated that we are in fact making some progress in this direction. We haven’t found our superhero, and I have no last-minute plot twist up my sleeve – but labs full of everyday heroes are on the case, and this story is bound to have many sequels over the years.