Inherited gene variation leaves young leukemia patients at risk for peripheral neuropathy
Researchers have identified the first genetic variation that is associated with increased risk and severity of peripheral neuropathy following treatment with a widely used anti-cancer drug. Investigators also found evidence of how it may be possible to protect young leukemia patients without jeopardizing cures. St. Jude Children’s Research Hospital scientists led the study, which appears today in the Journal of the American Medical Association.
The study involved 321 children and adolescents whose acute lymphoblastic leukemia (ALL) treatment included between 36 and 39 doses of the drug vincristine.
Researchers screened patient DNA for almost 1 million common inherited genetic variations and found that 60.8 percent of those who inherited two copies of a variation in a gene named CEP72 developed peripheral neuropathy. Vincristine-related peripheral neuropathy was diagnosed in 23.4 percent of patients who inherited at least one of the more common versions of CEP72. Patients with two copies of the high-risk CEP72 variant were also more than twice as likely as other patients to experience serious, disabling or life-threatening peripheral neuropathy.
The newly identified CEP72 variant also increased the sensitivity of cancer cells to vincristine. “That suggests it might be possible to lower the vincristine dose in these patients without compromising the likelihood of cures,” said the corresponding author William Evans, Pharm.D., a member of the St. Jude Department of Pharmaceutical Sciences. The possibility will be studied in a St. Jude clinical trial scheduled to open later this year for newly diagnosed pediatric ALL patients.
“St. Jude researchers have already achieved high cure rates for ALL. In this study, they identified a possible reason why some people experience a serious side effect of the medication - debilitating nerve pain,” said Rochelle Long, Ph.D., director of the National Institutes of Health Pharmacogenomics Research Network. “This genetic insight will help scientists devise treatment plans that ensure safety and effectiveness as well as the long-term quality of life for children with ALL.”
Vincristine is one of the most widely used and effective agents for treatment of leukemia, lymphoma, brain and solid tumors in children and adults. But in a significant number of children and adults, the drug causes episodes of peripheral neuropathy that can become chronic and resurface in adulthood. The symptoms, which include pain, numbness and other changes that make walking difficult, are often severe enough to delay treatment. Such delays can compromise the likelihood of a cure. Currently there is no way to identify patients who are most likely to develop the nerve damage.
What is peripheral neuropathy?
An estimated 20 million people in the United States have some form of peripheral neuropathy, a condition that develops as a result of damage to the peripheral nervous system - the vast communications network that transmits information between the central nervous system (the brain and spinal cord) and every other part of the body. (Neuropathy means nerve disease or damage.) Symptoms can range from numbness or tingling, to pricking sensations (paresthesia), or muscle weakness. Areas of the body may become abnormally sensitive leading to an exaggeratedly intense or distorted experience of touch (allodynia). In such cases, pain may occur in response to a stimulus that does not normally provoke pain. Severe symptoms may include burning pain (especially at night), muscle wasting, paralysis, or organ or gland dysfunction. Damage to nerves that supply internal organs may impair digestion, sweating, sexual function, and urination. In the most extreme cases, breathing may become difficult, or organ failure may occur.
Peripheral nerves send sensory information back to the brain and spinal cord, such as a message that the feet are cold. Peripheral nerves also carry signals from the brain and spinal cord to the muscles to generate movement. Damage to the peripheral nervous system interferes with these vital connections. Like static on a telephone line, peripheral neuropathy distorts and sometimes interrupts messages between the brain and spinal cord and the rest of the body.
Peripheral neuropathies can present in a variety of forms and follow different patterns. Symptoms may be experienced over a period of days, weeks, or years. They can be acute or chronic. In acute neuropathies such as Guillain-Barré syndrome (in which the body’s immune system attacks part of the peripheral nervous system and impairs sending and receiving nerve signals), symptoms appear suddenly, progress rapidly, and resolve slowly as damaged nerves heal. In chronic forms, symptoms begin subtly and progress slowly. Some people may have periods of relief followed by relapse. Others may reach a plateau stage where symptoms stay the same for many months or years. Many chronic neuropathies worsen over time. Although neuropathy may be painful and potentially debilitating, very few forms are fatal.
In diabetic neuropathy, one of the most common forms of peripheral neuropathy, nerve damage occurs in an ascending pattern. The first nerve fibers to malfunction are the ones that travel the furthest from the brain and the spinal cord. Pain and numbness often are felt symmetrically in both feet followed by a gradual progression up both legs. Later, the fingers, hands, and arms may become affected.
Overall 50 patients, or 16 percent of 321 those in this study, inherited two copies of the high-risk CEP72 variant. The study included 222 newly diagnosed patients enrolled in the St. Jude Total XIIIB clinical trial between 1994 and 1998. The remaining 99 patients were part of a Children’s Oncology Group (COG) study for relapsed patients. COG is the world’s largest organization devoted exclusively to childhood and adolescent cancer research.
The high-risk CEP72 variant identified in this study was linked to a greater risk of peripheral neuropathy even when researchers took other risk factors into account, including race and vincristine dose. Vincristine-related peripheral neuropathy is less common among African-American patients. Researchers found that the high-risk version of the gene is also less common in African-American patients, so they are less likely than patients from other racial backgrounds to inherit the high-risk version of CEP72.
How are the peripheral neuropathies classified?
More than 100 types of peripheral neuropathy have been identified, each with its own symptoms and prognosis. In general, peripheral neuropathies are classified according to the type of damage to the nerves. Some forms of neuropathy involve damage to only one nerve and are called mononeuropathies. More frequently however, multiple nerves are affected, called polyneuropathy.
Some peripheral neuropathies are due to damage to the axons (the long, threadlike portion of the nerve cell), while others are due to damage to the myelin sheath, the fatty protein that coats and insulates the axon. Peripheral neuropathies may also be caused by a combination of both axonal damage and demyelination. Electrodiagnostic studies can help healthcare providers determine the type of damage involved.
CEP72 carries instructions for assembling the CEP72 protein, which is essential for formation of the cellular machinery that ensures genetic material is divided properly during cell division. Vincristine targets the same process in cells.
The high-risk CEP72 variation occurs in a region of DNA that regulates gene activity and turns the gene on and off. In cells growing in the laboratory, investigators showed the high-risk variant was associated with reduced CEP72 activity and greater sensitivity to vincristine in human nerve cells and cancer cells, including ALL.
What Are the Types of Peripheral Nerves?
There are three types of peripheral nerves:
sensory nerves, which connect to your skin
motor nerves, which connect to your muscles
autonomic nerves, which connect to your internal organs
Peripheral neuropathy can affect one nerve group or all three.
What Are the Symptoms of Peripheral Neuropathy?
The symptoms of peripheral neuropathy include:
tingling in hands or feet
a feeling like you are wearing a tight glove or sock
sharp, stabbing pains
numbness in hands or feet
weak, heavy-feeling arms and legs (sometimes it may feel like your legs or arms “lock” in place)
regularly dropping things from your hands
a buzzing or shocking sensation
thinning of the skin
a drop in blood pressure
sexual dysfunction, especially in men
constipation
digestion difficulties
diarrhea
excessive sweating
Evans and his St. Jude colleagues have pioneered the use of pharmacogenetics to enhance the safety and effectiveness of chemotherapy by studying how inherited differences in the makeup of genes influence patients’ response to drugs. “Today at St. Jude, 94 percent of newly diagnosed ALL patients will be alive in five years,” Evans said. “The challenge now is to maintain and improve cure rates while improving the quality of life for children during treatment and beyond.”
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The study’s first author is Barthelemy Diouf, of St. Jude. The other authors are Kristine Crews, Deqing Pei, Cheng Cheng, Ju Bao, Jie Zheng, Wenjian Yang, Yiping Fan, Steven Paugh, Joseph McCorkle, Ching-Hon Pui and Mary Relling, all of St. Jude; Glen Lew, Emory University, Atlanta; Heather Wheeler, Claudia Wing, Shannon Delaney, Masaaki Komatsu and M. Eileen Dolan, all of University of Chicago; Xiaomin Lu and Meenakshi Devidas, both of University of Florida, Gainesville; Naomi Winick, University of Texas Southwestern School of Medicine, Dallas; William Carroll, New York University Cancer Institute; Mignon Loh, University of California School of Medicine, San Francisco; and Stephen Hunger, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora.
The study was funded in part by grants (CA36401, GM92666, GM61393, CA136765, CA165823, CA21765, CA98543, CA98413, CA114766) from the National Institutes of Health and by ALSAC.
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