People with an inherited disease known as neurofibromatosis type 1 (NF1) often develop benign, or non-cancerous, tumors that grow along the nerves. Sometimes these tumors can turn into aggressive cancers, but until now there was no good way to determine if this transformation into cancer had occurred .
Researchers at the Cancer Research Center of the United States National Cancer Institute (NCI), part of the National Institutes of Health, and the University of Washington School of Medicine, have developed a blood test that, they believe it could one day offer a very sensitive and inexpensive method of detecting cancer early in people with NF1. The blood test could also help doctors monitor patients’ response to cancer treatment, as published in the journal PLOS Medicine.
NF1 is the most common cancer predisposition syndrome, affecting 1 in 3,000 people worldwide. The disease, caused by a mutation in a gene called NF1, is almost always diagnosed in childhood. About half of those affected develop large but benign tumors on the nerves, called plexiform neurofibromas.
In up to 15% of people with plexiform neurofibromas, these benign tumors develop into an aggressive form of cancer known as a malignant peripheral nerve sheath tumor (TMVNP). These patients have a poor prognosis because the cancer can spread rapidly and often becomes resistant to both chemotherapy and radiation. The 80% of people who are diagnosed with MPNST die within five years.
“Imagine going through life with a cancer predisposition syndrome like NF1. It’s kind of like a time bomb, exemplifies study co-author Dr. Jack F. Shern, Lasker Clinical Research Fellow in Pediatric Oncology. Doctors are going to watch out for cancerous tumors, and you are going to watch out for them , but you really want to discover that transformation into cancer as soon as possible. ”
Currently, doctors use imaging scans (MRI or PET) or biopsies to determine whether plexiform neurofibromas have transformed into TMVNP. However, biopsy results are not always accurate, and the procedure can be extremely painful for patients because tumors grow along the nerves. The imaging tests , meanwhile, are expensive and can also be inaccurate.
“What we don’t have right now is a tool to help us determine if something bad is cooking up inside that big, bulky benign plexiform neurofibroma and turning into a TMVNP, explains Dr. Shern. So we thought, ‘So if we develop a simple blood test where instead of a whole body MRI or fancy positron emission tomography scan , we can just draw a tube of blood and tell whether or not the patient has a TMVNP somewhere ? ”
To achieve this goal, Shern and the study’s co-directors, Dr. Aadel A. Chaudhuri and Dr. Angela C. Hirbe of the University of Washington School of Medicine, and their colleagues, collected blood samples from 23 people with neurofibromas. plexiforms, 14 patients with TMVNP who had not yet been treated and 16 healthy people without NF1.
Most of the study participants were adolescents and young adults, the age group in which TMVNP most often develops. The researchers isolated cell-free DNA – that is, DNA that is shed from cells in the blood – from blood samples and used whole genome sequencing technology to look for differences in genetic material between the three groups.
The cell-free DNA of the patients with TMVNP exhibited several characteristics that distinguished it from the DNA of the other two groups. For example, patients with TMVNP had shorter chunks of cell-free DNA than those of people with plexiform neurofibromas or without NF1.
Furthermore, the proportion of cell-free DNA that comes from tumors – called the ‘plasma tumor fraction’ – in blood samples was much higher in people with TMVNP than in those with plexiform neurofibromas. Together, these differences allowed the researchers to differentiate, with 86% accuracy, between patients with plexiform neurofibromas and those with TMVNP.
In study participants with TMVNP, the plasma tumor fraction also aligned with how well they responded to treatment. In other words, if their plasma tumor fraction decreased after treatment, the size and number of their tumors (as measured by imaging scans) also decreased . An increase in the plasma tumor fraction was associated with metastatic recurrence.
“You can imagine treating a patient with a chemotherapy regimen. This blood test would allow us to quickly and easily determine if the disease is decreasing or even disappearing completely, Shern notes. And if a TMVNP had been operated on and removed, and If the blood test is negative, it could be used to monitor the patient in the future to see if the tumor reappears. ”
Dr Shern stresses that one of the limitations of the current study is its small size, although it included people with NF1 from two large hospitals. The researchers plan to conduct a larger trial with more patients. Shern notes that the team’s goal is to increase the accuracy of the blood test from 86% to close to 100%. One approach would be to refine the genetic analysis to focus on genes known to be involved in TMVNP.
A simple and inexpensive blood test to detect TMVNP early in patients with NF1 would be especially useful in developing countries and other under-resourced areas, where access to the equipment and knowledge necessary for imaging is limited adds the doctor.
Blood tests of this type also have applications in the early detection and follow-up of patients with other genetic disorders that predispose to cancer, such as multiple endocrine neoplasia, in which benign tumors can become cancerous, or Li syndrome. Fraumeni, which increases the risk of developing various types of cancer.
“This is the perfect opportunity to apply these technologies where we can use a simple blood test to examine a population at high risk. If the test shows something abnormal, that’s when we know we need to act and go looking for a tumor.”