Nancy A. Melville

May 14, 2015

Washington, DC — Key genetic mutations that appear to be distinctive to the small subset of benign neurofibromas in type 1 neurofibromatosis (NF1) that convert to potentially deadly malignant peripheral nerve sheath tumors (MPNSTs) may help pave the way for a noninvasive biomarker for these malignant tumors, researchers say.

"One of the challenges in NF1 and MPNST is detection and diagnosis of a malignancy, particularly in individuals with a pronounced phenotype with multiple neurofibromas," explained first author Chetan Bettegowda, MD, from Johns Hopkins University in Baltimore, Maryland.

"Using anatomic imaging, such as magnetic resonance imaging (MRI) or positron emission tomography (PET), can be challenging."

The stakes, meanwhile, are high — among the approximately 10% to 15% of people with NF1 who develop MPNST, the 5-year survival rates are as low as 20%.

The researchers reported their findings here at the American Association of Neurological Surgeons (AANS) 83rd Annual Meeting.

Malignant Conversion

To try to identify the genetic change that occurs in the conversion from benign to malignant neurofibromas, Dr Bettegowda and his colleagues performed genetic testing on 50 cases of MPNSTs compared with 11 cases of matched but benign neurofibromas.

Immunohistochemistry testing showed that as many as 16 of the MPNSTs had a striking and consistent distinction — somatic mutations in the chromatin-modifying gene SUZ12 — which none of the benign neurofibromas showed.

MPNSTs without SUZ12 alterations also had somatic mutations in other members of the polycomb repressor complex 2 (PRC2), in which SUZ12 belongs; PRC2 is a key epigenetic regulator of cellular transcription, Dr Bettegowda said.

In all cases showing SUZ12 mutation, there was an abolishment of protein expression and the loss of the H3K27 trimethylation, which is a downstream target of SUZ12, an indication that the alterations were having the effect of inactivating of protein function.

The findings were published last year in a paper in Nature Genetics.

"Our results suggest that SUZ12 and other members of the PRC2 complex, which is a central regulator of cellular epigenetic machinery, play a critical role in the transformation of benign neurofibromas into MPNSTs," Dr Bettegowda concluded.

In more recently following up on the findings, the authors turned to digital genomics with the question of whether cell-free DNA with the PRC2 complex mutations could represent a broadly applicable cancer biomarker, detectable in plasma.

They evaluated more than 400 samples of tumor tissue taken at the time of surgery, identifying genetic alterations and then looking for the matching alteration in plasma.

In a small but important cohort of 3 cases of MPNST, the researchers found that mutations of PRC2 complex genes were indeed identified in the plasma.

"We are now performing ongoing studies to follow-up on this and see if these levels correlate to disease status over time," Dr Bettegowda said.

"Potentially these alterations at the DNA level could be used as biomarkers for the disease. Certainly more collaborative studies are needed to answer this."

Dr Bettegowda noted that similar findings on SUZ12 were reported at about the same time as his research, including a study from researchers at the Memorial Sloan-Kettering Cancer Center in New York.

Cancer Screening

Commenting on the pursuit of a biomarker for MPNSTs, Michael Glantz, MD, a neurologist with the Penn State Milton S. Hersey Medical Center in Pennsylvania, noted that while cancer screening tools have come under increasing scrutiny, the tumors in question — MPNSTs — fall into a different category.

"Screening studies have gotten a lot of bad press lately for a couple of reasons. One is the cancers may be relatively uncommon, such as lung cancer, and another reason is that with the more common cancers, like breast and prostate cancer, outcomes are often not that bad, even if we diagnose people late."

"But neither of these issues apply to MPNSTs — these are relatively common and they are relatively bad."

Kimberly Harbaugh, MD, an associate professor of neurosurgery also at Penn State Hershey Neurosurgery, agreed that the findings are important, particularly in light of the serious nature of MPNST.

"[MPNST] has a poor prognosis and doesn't respond well to our current chemotherapy and radiation treatment regimens," she told Medscape Medical News.

"If we can find a new way to approach the treatment of these by understanding the genetics associated with their development, we may be able to improve patient survival."

She noted that, importantly, the removal of benign tumors presents a challenge that prevents them being pre-emptively excised out of concern of their becoming malignant, Dr Harbaugh added.

"Removal of plexiform neurofibromas often leads to numbness or weakness, and patients often have progression of the plexiform neurofibromas over their lifetime," she said. "So taking them out simply because of the remote risk of malignant degeneration is not feasible."

Regarding the new findings, Dr Harbaugh said it's also important to consider that the PRC2 complex acts as both a tumor promoter and tumor suppressor depending on the tumor type.

"So it remains to be seen whether treatment of one tumor type in some populations could theoretically lead to the development/growth of a different tumor type."

Nevertheless, discussant Robert J. Spinner, MD, a neurosurgeon with the Mayo Clinic, Rochester, Minnesota, put into context the potential importance of advances in MPNST detection and understanding.

"Over the past few decades, much scientific work and many molecular advances have been made with benign neurofibromas in patients with neurofibromatosis 1," he said. "In contrast, only a few major gains have occurred with MPNSTs — until now."

"This is an exciting finding and exciting time but an exciting first step," he said.

Dr Bettegowda and Dr Harbaugh have disclosed no relevant financial relationships. Dr Glantz's disclosures include consulting for AbbVie Pharmaceuticals and receipt of an honorarium from SigmaTau Pharmaceuticals. Dr Spinner has been a consultant for Mayo Medical Ventures and received an honorarium from Oakstone Publishers.

American Association of Neurological Surgeons (AANS) 83rd Annual Meeting. Abstract 726. Presented May 4, 2015.

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