AnneMarie Ciccarella, a fast-talking 57-year-old brunette with more than a hint of a New York accent, thinks she knows 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 cancerous, she immediately got tested for mutations in the two BRCA genes, which between them account for up to 20 percent of families with a history of a strong account of the breast. crab.
Ciccarella thinks its results will be positive. They are not. Instead, they only identify what’s known as a variant of unknown or uncertain significance (VUS)—or two of them, one in both BRCA1 and BRCA2. Unlike pathogenic mutations that are known to cause disease or benign ones that do not, these genetic variations are not known enough to know whether they cause problems or not.
“I think you may or may not have a mutated gene, and with all the cancer in my family, I believe I will carry a mutation. I didn’t know there was this great third category,” he said. “I have no idea – it feels like a huge waste of blood to get a big question mark.”
Thousands of people have had their BRCA genes tested for an increased genetic susceptibility to breast, ovarian, prostate and other cancers. About five percent learned they carried a VUS. That number can be even higher for other genes: in one studyalmost 20 percent of genetic tests return a VUS result.
“That’s a lot of uncertainty,” says Robert Klitzman, a geologist at Columbia University in New York. People want genetic tests to be like pregnancy tests, he explains: “You’re either pregnant or you’re not. Instead, they are like weather reports. ” And most people are not prepared to face the possibilities and uncertainties involved.
When scientists studied a group of women a year after they received their BRCA genetic test results, women whose results were uncertain or ambiguous felt significantly more stress and anxiety than those whose results were positive. clearly either pathogenic or benign. Subsequent research shows that the higher the risk an individual thinks the outcome indicates, and the less tolerance there is for uncertainty, the more likely they are to experience significant long-term distress.
Even before her follow-up results came in, Ciccarella had decided on a cancerous mastectomy based on her family history. For her, the question of whether she will develop breast cancer one day has been answered, and in the worst way possible. But she also wants information for her son and daughter so they can know if they have inherited a genetic risk of cancer. Like a number of families, they are learning that genetics will not provide answers for everyone.
There are differences in genes
We are all organic. The three billion pieces of DNA that make us who we are are usually, chiselled in granite like a classical monument, with only minor changes made here and there. Scientists used to believe that DNA mutations were very harmful.
In the late 1990s and early 2000s, as the main sequences of the human genome were changing, researchers realized that their view of the mutations was completely backwards. Instead of being passive and almost injurious to health, free-transitions preserve human characteristics. The average person carries around 400 unique mutations, and most of us are not bad because of them.
This addresses some of the basic principles of genetics, as well as the ways scientists and doctors interpret genetic tests.
When Robert Resta, a genetic counselor at the Swedish Medical Center in Seattle, first began to examine the results of genetic testing in the late 1980s, he could only identify chromosomal abnormalities or changes of a large amount of DNA. When other types of genetic tests are introduced, such as those for detecting mutations in the CFTR gene that cause cystic fibrosis, the interpretation is also straightforward. Because the majority of people who have their CFTR gene regulated show clinical signs of cystic fibrosis, Resta can be confident that the observed change in the gene is the one that leads to the disease. In the past few years, however, the cost of genetic testing has dropped dramatically, and doctors are asking for DNA testing earlier in the diagnostic process. As we gather more data, the sheer number of changes we all make becomes more important.
“It turns out that changes are the norm. You hope to find changes in a gene. It’s a very different way of thinking about humanity. If you don’t see a change, your device may have a technical problem,” Resta said.
When scientists test for mutations in large numbers of genes with a test, known as a gene panel, they are almost guaranteed to find at least one VUS, says Colleen Caleshu, a genetic counselor at Ile -Stanford University Center for Inherited Inherited Disease. “The more genes you look at, the more variation you’ll see,” he added. “We all have many variations in our genes, most of which are very rare and, by their imperfect nature, we cannot interpret.” In short, there is not enough data to know what you see.
This gray area has only expanded as DNA sequencing has led to the use of multiple panels, to look for mutations in various genes that may be related to a patient’s symptoms. Of the three possible outcomes — pathogenic, benign, or unknown — pathogenic is the least likely, Resta said. It is more likely to have uncertainty.
If interpreting genetic test results is difficult for physicians, it is also very difficult for patients. Yvonne Bombard has spent the last several years of her career as a genomics health services researcher at St. Michael’s Hospital in Toronto, working to understand how families make sense of genetic test results.
“There is little research on the impact of uncertain outcomes on families yet – the technology is very new,” Bombard said.
A little research is Psycho-oncology studied 24 women with breast or ovarian cancer who had received VUS results for their genetic testing. Most of them have a wrong understanding of what those results mean. Although two-thirds correctly remembered three years later that the test’s differences were indistinguishable, 79 percent interpreted the results as a higher genetic risk for developing cancer. A third had also made significant medical changes in their lives based solely on their test results, which Resta and Caleshu did not recommend.
Families of children with suspected genetic diseases have similar problems. Parents tend to interpret any variation that is not categorized as ‘abnormal’ as the cause of their child’s disease, Caleshu explains. But she appreciates how hard it is not to do that, especially when families have been searching for answers for so long.
Families can be motivated by the medical establishment, who seem to raise their hands when a patient ignores a diagnosis, and without specific answers it is very easy to believe that the genetic differences identified on the test must be what is wrong. One of Caleshu’s main functions is to provide pre-test counseling so that patients understand the risks and limitations of the test. He said his team has changed the way they present the results, so that patients and doctors don’t read too much into a VUS. Even with the right genetic counseling, however, the uncertainty can be painful.