The long read: With so many unknowns in our DNA, using genetics in medical testing doesnt always bring the answers sometimes it brings only doubt
AnneMarie Ciccarella, a fast-talking 57-year-old brunette with more than a hint of a New York accent, thought she knew a lot about breast cancer. Her mother was diagnosed with the disease in 1987, and several other female relatives also developed it. When doctors found a suspicious lump in one of her breasts that turned out to be cancer, she immediately sought out testing to look for mutations in the two BRCA genes, which between them account for around 20% of families with a strong history of breast cancer.
Ciccarella assumed her results would be positive. They werent. Instead, they identified only whats known as a variant of unknown or uncertain significance (VUS) in both BRCA1 and BRCA2. Unlike pathogenic mutations that are known to cause disease, or benign ones that dont, these genetic variations just arent understood enough to know if they are involved or not.
I thought you could have a mutated gene or not, and with all the cancer in my family, I believed I would carry a mutation. I didnt know there was this huge third category, she says. I got no information it felt like a huge waste of blood to get a giant question mark.
Thousands of people have had their BRCA genes tested for increased genetic susceptibility to breast, ovarian, prostate and other cancers. About 5% have learned that they carry a VUS. That number is even higher for other genes: in one study, almost 20% of genetic tests returned a VUS result.
Thats a lot of uncertainty, says Robert Klitzman, a bioethicist at Columbia University in New York. People want genetic tests to be like pregnancy tests, he explains: Youre either pregnant or youre not. Instead, theyre more like a weather report. And most people arent prepared to cope with the probabilities and uncertainties that entails.
When scientists surveyed a group of women one year after they received BRCA gene test results, the women whose results were uncertain or uninformative were feeling much more stress and anxiety than those whose results were clearly either pathogenic or benign. A follow-up study showed that the higher the risk an individual thought her result indicated, and the less tolerant she was of uncertainty, the more likely she was to experience serious long-term distress.
Even before her sequencing results came in, Ciccarella had decided on a bilateral mastectomy, based on her family history. For her, the question of whether she would one day develop breast cancer had been answered, and in the worst possible way. But she still wanted information for her son and daughter so they could know if they had inherited a genetic risk of cancer. Like a number of families, they are learning that genetic sequencing wont deliver answers for everyone.
We are all mutants. The 3bn pieces of DNA that make us who we are were long thought to be constant, chiselled in granite like a classical monument, with only tiny changes made here and there. Scientists used to believe that DNA mutations were largely harmful.
By the late 1990s and early 2000s, as the first sequences of the human genome came rolling in, researchers realised that their view of mutations was completely backwards. Instead of being rarities that almost inevitably harm health, mutations litter the human genome. The average human carries around 400 unique mutations, and most of us are none the worse because of them.
This challenged some basic tenets of genetics, as well as they ways that scientists and physicians interpreted genetic tests.
When Robert Resta, a genetic counsellorat the Swedish Medical Center in Seattle, first began examining genetic test results in the late 1980s, he could identify only chromosomal abnormalities or alterations of massive amounts of DNA. When other types of genetic tests were introduced, such as those for detecting the mutations in the CFTR gene that cause cystic fibrosis, interpretation was still reasonably straightforward. Because most of the people who had their CFTR gene sequenced showed clinical signs of cystic fibrosis, Resta could be reasonably confident that an observed mutation in that gene was the one that had led to the disease. In the past few years, however, the price of genetic sequencing has fallen dramatically, and doctors are increasingly requesting DNA testing earlier in the diagnostic process. As more data is gathered, the sheer number of mutations we all carry becomes more significant.
It turns out mutations are the norm. You expect to find mutations in a gene. Its a very different way of thinking about the human genome. If you dont find a mutation, your machine is probably having technical difficulty, Resta says.
When scientists test for mutations in large numbers of genes with a single test, known as a gene panel, they are virtually guaranteed to find at least one VUS, says Colleen Caleshu, a genetic counsellor at Stanford Universitys Center for Inherited Cardiovascular Disease. The more genes you look at, the more variation youll find, she adds. We all have tons of variations in our genes, most of which are extremely rare and, by the very nature of rarity, uninterpretable. In short, there isnt enough data to know what you are seeing.