Published April 10, 2013
Each cancer patient’s response to chemotherapy is unique. Some may experience nausea and immune deficiency, while others can experience a more severe adverse condition known as chemotherapy-induced peripheral neuropathy (CIPN) – a form of nerve damage that can be so debilitating, it often prompts patients to stop treatment early.
Doctors have had a hard time predicting which patients will ultimately develop CIPN, making it difficult to tailor treatment so that it is most effective for each individual. But now, new research has revealed seemingly benign genetic mutations that may influence who develops this painful side effect.
In a study from the Mayo Clinic Cancer Center, researchers have implicated the genes EPHA5, ARHGEF10 and PRX as playing significant roles in the development of CIPN. This discovery can ultimately help doctors to have a better understanding of CIPN and whether or not their patients should move forward with certain cancer treatments.
“Chemotherapy-induced peripheral neuropathy is one of the most important, unmitigated side effects of chemotherapy,” lead author Dr. Andreas Beutler, an oncologist at the Mayo Clinic Cancer Center, told FoxNews.com. “You have some other side effects that used to be very important – such as nausea and immune deficiency – but special medications have been developed. With CIPN, it has actually become the most prominent and troubling side effect for many chemotherapy patients, because there is no medication for it.”
Peripheral neuropathy is caused by damage to the peripheral nerves, which are furthest away from the brain and spinal cord. When chemotherapy damages these nerves, the condition becomes CIPN. Symptoms vary in type and intensity depending on which peripheral nerves are damaged, but they typically include shooting pain, burning, tingling or electric shock-like pain, loss of feeling, balance issues and muscle weakness. The symptoms can become so severe that patients lose the ability to walk normally and are left with permanent numbness in their extremities.
CIPN affects an estimated 30 to 40 percent of patients, but there is no current way to determine who will experience it – or how severe it will be.
Beutler and his colleagues decided to analyze the genetics of cancer patients through exome sequencing - a form of DNA analysis that selectively sequences the parts of the genome responsible for coding functional proteins. Known as the exonic region, this area is estimated to house 85 percent of all disease-causing genetic mutations.
The researchers performed exome sequencing on 20,794 genes from 119 cancer patients. Half of the patients were experiencing CIPN during their chemotherapy trial.
“The genome is three billion nucleotides, meaning the whole genome has three billion different positions,” Beutler said. “Out of those, we assessed 60 million of each patient… that are best understood –the exome. Thereby, we could get a very good view of the part of the genome that is most important and most relevant to our question.”
Exome sequencing of the more than 20,000 genes lead the researchers to EPHA5 – a previously implicated gene in hereditary peripheral neuropathy – as well as two new genes ARHGEF10 and PRX. Genetic mutation in all three areas was associated with a predisposition to CIPN.
While the genes are responsible for a number of functions, all seem to share a common denominator when it comes to the peripheral nervous system.
“They have known roles in regulating and maintaining the peripheral nerves,” Beutler said of the three genes’ functions. “They all seem to be involved in regulating the process of producing myelin – which is important for the integrity of the peripheral nervous system.”
Beulter ultimately hopes this discovery will pave the way for more use of genomic medicine in the future. For cancer patients, physicians can potentially use their genetic code to determine the treatment most suited for them, as well as one that is most tolerated.
“There are certainly very different situations,” Beutler said. “Sometimes there’s a treatment that would cause terrible side effects, but it would be the only approach to prolong life and cure cancer. Even then, it is important for some patients to really have the best picture of understanding how treatment will impact their life… You could make a case that if you can predict which treatment a patient can tolerate best, then that will be helpful in deciding how to move forward.”
And Beutler does not discount the idea that his study may have an even more significant impact down the road.
“The hope certainly is this kind of research will contribute to treatments that will reduce CIPN – similar to how we have treatments to treat symptoms of nausea or immune deficiency,” Beutler said.
Results of the Mayo Clinic study were presented April 9 at the American Association for Cancer Research annual meeting in Washington D.C.