Q&A: Neurofibromatosis and Its Relationship to Cancer

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Neurofibromatosis is worthy of study, say cancer and genetic experts, because the DNA mutations that cause its three types may yield crucial information about how cancer develops -- and new approaches to cancer treatment.

John Slopis, M.D.
, associate professor in the Department of Neuro-Oncology and medical director of the MD Anderson's Neurofibromatosis Program, explains the basics of the disease. (See related story on NF patient Reggie Bibbs.)

What is neurofibromatosis?
Neurofibromatosis is a name given to three different genetic conditions: neurofibromatosis 1, neurofibromatosis 2 and multiple schwannomatosis. These conditions are all called neurofibromatosis or NF because they all cause tumors to grow on nerves.

What is neurofibromatosis 1?
Neurofibromatosis type 1 involves tumors of the nerves from the spine to any extremity and including the skin, tumors of nerves in some organs and tumors of the optic nerves (from the eyes to the brain). NF 1 is also associated with other complications, including bone tumors, spinal scoliosis, high blood pressure, short stature (limited growth in children), brain tumors and learning disabilities.

The genetic mutation is found on chromosome 17 and is inherited from either the mother or the father. In half of the cases, the person with NF 1 will be the first born in the family, who can then pass the gene for NF 1 on to his or her children. People with NF 1 have a great variety of different symptom patterns.

What about NF 2?
Neurofibromatosis type 2 is also genetic, passed down in the same pattern as NF 1, but the genetic mutation is on a different chromosome -- chromosome 22. The disorder is quite different from NF 1.

In NF 2, tumors grow on any nerve from the spine or brainstem. The disorder is diagnosed clinically by loss of hearing or dizziness in the patient due to growth of tumors on the acoustic nerves (these are called 8th nerve schwannomas).

Tumors can grow on other structures in the spinal cord (ependymomas) or on the bone of the skull (meningiomas). Tumors of the spine can be very serious. Most people with NF 2 have very similar patterns of problems. NF 2 does not cause the other complications seen in NF 1.

And the third type of neurofibromatosis?
Called multiple schwannomatosis, it looks a lot like NF 2. But these tumors of the nerves never occur in the brain, brain stem or anywhere above the neck. We know there is one gene mutation that causes it in about a third of cases. This gene mutation is called INI-1. It was only recently discovered. The other two-thirds of cases must be caused by gene mutations, but we have not yet identified these. This condition is best known because it causes patients to experience a great deal of nerve-related pain.

What is the connection with cancer or cancer treatment? 
Most of the tumors of NF are benign tumors that grow slowly and do not become malignant. This means that these tumors are a lot like normal tissue. However, when they grow in the wrong place, the mass of the tumor causes problems. These can cause pressure on the nerves to the ear or eye, spinal cord, brain stem or brain. Sometime the tumors cause pain. Only NF 1 tumors are known to transform into serious malignant cancers called malignant peripheral nerve sheath tumors.

The connection with cancer is that many cancers result from mutations of normal DNA. If we can work out the way a mutation changes the growth of a normal tissue into a tumor or cancer, we can find clues to help cure the cancer.

What types of research are you conducting in the Neurofibromatosis Clinic at MD Anderson?
We're evaluating the use of positive emission tomography/computed tomography imaging (PT/CT), both of which provide three-dimensional images of functional processes in the body, to identify tumors in the early stages of malignant transformation.

We're working on whole-gene sequencing of the NF 1 gene to identify specific mutations that predict the development of malignancy in a given patient with NF.

And we're attempting to characterize the tumor genetics and signaling mechanisms of NF1 and NF 2. We hope to discover more targeted systemic therapies, which home in on the condition's distinct biological pathways.

Related story:
Go Ahead Ask: Neurofibromatosis Patient Invites Questions, Makes Friends
A Houston-based, internationally known activist, Reggie Bibbs has neurofibromatosis type 1, a genetic disorder that ranges in severity from almost imperceptible to major.Read more about Reggie


I and my 3 children have schwannomatosis.
You say in your Q&A answer that in
schwannomatosis no tumors form above the neck - we have all had tumors on the cranial nerves mainly the 5th nerve.
You also state that only in NF1 do tumors turn malignant. I lost one child to soft cell sarcoma - a schwannoma turned malignant.
Another of my children also has several malignant schwannoma's.
We have had blood tests - supervised by Dr Gareth Evans in Manchester UK - which confirm schwannomatosis.

Dr. Slopis' sent me his reply to the comment below.

Rob brings up an interesting and important point. His family appears to have one of the less common forms of schwannomatosis. Though it's difficult for me to comment without knowing which genetic studies were used and which gene was identified, rare cases of this type do exist in the general category "schwannomatosis."

The general clinical descriptions of the different forms of neurofibromatosis are useful guides in discussion and diagnosis of NF but there are always exceptions. This is why ongoing studies of genetic mutations in NF are so important for diagnosis. Sometimes the symptoms of clinical cases of NF overlap with other forms of NF and even with other disorders. For example, NF1 and NF 2 patients may both have cafe au lait spots. Some children with cafe au lait spots and attention deficit disorder (common features of NF 1) may actually have Legius syndrome (a mutation of the SPRED 1 gene) or they may have McCune Albright syndrome (gene mutations patterns are not completely defined).

Most cases of NF 1 can be confirmed by genetic testing at this time (revealing a mutation on chromosome 17). Only about 70% of NF 2 cases can be confirmed by genetic testing at this time (revealing a mutation on chromosome 22). This means around 30% of people with NF 2 carry some other genetic mutation as the cause of their symptoms.

Schwannomatosis is the least understood condition of the group. Recently some schwannomatosis patients were found to have a genetic mutation called INI-1 or SMARC-B1. This mutation is thought to account for around 1/3 of schwannomatosis patients, but there is not yet enough information to confirm this number. This was a somewhat surprising finding because the SMARC mutation was first associated with soft tissue sarcomas, not schwannomas. This may be one of the connections between the commonly benign schwannomas and the more rare cases of schwannomas that become malignant.

--John Slopis, M.D.

My son Mathew age 31 has NF1 which was diagnosed in January 2011. However in September 2009 he started to get tingling and numbness in his left lower leg/ankle.
This started our cancer treatment voyage here in the UK. The fact is the biopsy was described as a pleomorphic sarcoma of the sacrum revised to be a High Grade Spindle Cell sarcoma.
Currently he is in a hospice as he is untreatable and incurable.
I would like to know if NF sufferers actually get other types of cancer apart from MPNST.
I srongly suspect my son's cancer came from nerve tissue so should be correctly diagnosed as a MPNST.
David Young age 65 Frimley Surrey UK.

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