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When tragedy strikes, physicians are often asked to answer two questions. The first is the how question. How did this happen? Long illnesses provide time for patients and family members alike to come to terms with a diagnosis and prognosis. Not always, and not easily, but the time is there. In the case of sudden cardiac death in a young person, there is no time. Sudden cardiac death is a condition that feels out of place in 2016. That a healthy person can be alive and then, simply, not, feels wrong to modern sensibilities. Nevertheless, the incidence of sudden cardiac death, about 1 per 100,000 young people per year is similar across multiple countries and cultures. Now a manuscript appearing in the New England Journal of Medicine attempts to shed light on how sudden cardiac death can happen. For the video version of this post, click here.
The researchers examined literally every case of sudden cardiac death occurring in individuals less than age 35 in Australia and New Zealand from 2010 to 2012 in a prospective fashion. With each of the 490 cases, they examined autopsy and toxicology reports to determine how the death occurred. While 60% of the cases were explainable by conditions like coronary artery disease and hypertrophic cardiomyopathy, a disturbing 40% had no revealing findings.
So they expanded the search, in a subset of that 40%, the researchers performed advanced genetic sequencing to look for gene mutations that could predispose to sudden death. They found mutations of that type in 27% of the otherwise unexplained cases. While the gap of understanding was narrowed a bit, the how question remained unanswered for many individuals.
Now I should mention that identifying disease-causing mutations is not as easy as it sounds. Most of the mutations identified were classified as “probably pathogenic”. Basically, that means that the mutations are predicted to do harmful things to the protein they affect, but we don’t know for sure at this time.
To take the analysis a step farther, the researchers examined family members of the deceased to screen for the presence of heritable cardiac conditions. In 12 of 91 families screened, such a condition – like long QT syndrome – was found.
So what we have here is a great example of a well-conducted, methodical, and meticulous study that has moved us incrementally towards greater understanding. For some of the families who suddenly lost a loved one – the answer to “how did this happen” is now clear.
Of course that’s only one of the two questions we get asked. The other is “why did this happen”? And that’s a question that no methodology, no matter how advanced, can answer.
For the video version of this post, click here. The prevailing wisdom about almost all types of cancer is that the disease occurs due to a combination of genetic susceptibility and environmental exposures. For different types of cancers, the relative weight of each of these components may differ. But teasing out how much contribution to cancer incidence can be attributed to genetics versus environment is tricky. Unless, that is, you have access to a register of over 100,000 pairs of twins.
In an article appearing in the Journal of the American Medical Association, researchers from four Nordic countries combined national twin registries to create a very detailed database of cancer incidence. The idea here is that identical twins share 100% of the genetic risk factors for cancer (whatever those may be), while fraternal twins share only 50%. This knowledge in hand, you can deconstruct just how much genetics is to blame for cancer.
First some numbers.
32% of the cohort would develop at least one cancer in their lifetime - a number which pretty closely matches what we see in the US.
Now, if your fraternal twin developed cancer, your lifetime risk bumped from 32% to 37%. If your identical twin developed cancer, that lifetime risk went from 32% to 46%. Clearly, genetics are at play here. But how much, exactly? Well, overall, the researchers estimate that about 33% of the variance in cancer incidence is due to genetic factors, with 0% due to shared environmental factors.
Let's parse that a bit though.
First, the researchers are NOT saying that the environment has nothing to do with cancer. They are saying that shared environmental factors, those things that two siblings would experience together, don't account for much risk. Once you leave the nest, in other words, the environment can still play a role. In fact, just doing the math suggests that around 66% of the variance in cancer incidence is due to environmental factors – just factors that don't happen to be shared by two siblings in their youth.
But as I mentioned, these contributions vary by type of cancer. For lung cancer, the shared environmental exposures accounted for more of the variance than genetics – probably because twins tend to share smoking habits even at a young age.
The important thing about this study is to realize that the genetic factor percentage puts a cap on what we can hope to learn from genetic studies of cancer. In other words, even if we perfectly sequenced everyone's genome, we'd only explain a third of the reasons why people get cancer. The smart money remains on evaluating environmental exposures, with the exception of some types of cancer that appeared to have very high genetic risks such as leukemia.
I'd be remiss if I didn't mention that this study was done in four Nordic countries and so the results probably don't give a complete picture of the risks faced in a more multi-ethnic society. In addition, the study can't answer the intriguing question of whether certain environmental exposures interact with certain genes to promote cancer. For now, we simply know that some of your destiny lies in your genes, but more of it in your actions.