Genetic signature for Rhabdoid meningioma discovered

Meningiomas are the most common primary brain tumors, but the term encompasses over a dozen subtypes that range from benign to highly aggressive. Rhabdoid meningiomas are classified as highly aggressive due to their high rates of recurrence and mortality, but the experience and outcomes for patients with this rare form of brain tumor vary widely. Researchers from Brigham and Women’s Hospital, in collaboration with colleagues at Massachusetts General Hospital, have identified genetic mutations in this form of brain cancer that can distinguish aggressive rhabdoid meningiomas from more benign forms using routine laboratory tests. The work is published in the journal Neuro-Oncology.

BAP1 immunohistochemistry of a rhabdoid meningioma
sample from a patient that carries a BAP1 mutation. The
protein is completely lost in the tumor cells but is still fully
maintained in normal blood vessel cells and in infiltrating
fibroblasts and immune cells.
Credit: Sandro Santagata, Brigham and Women’s Hospital

Usually, rhabdoid meningiomas are classified based on physical appearance and characteristics, but these enigmatic tumors can be difficult for pathologists to accurately classify. To find a molecular fingerprint that could help identify rhabdoid meningioma, Santagata and his colleagues sequenced 560 cancer-related genes from 14 meningiomas. In one sample, the team detected a mutation in the BAP1 gene along with telltale physical features (such as the shape of the tumor cells) of rhabdoid meningioma. Previous studies had found that people with inherited mutations in the BAP1 gene that cause a loss of BAP1 protein are prone to a tumor predisposition syndrome – a condition that puts them at a very high risk of developing several kinds of tumors including tumors in the eye, lung, kidney and elsewhere. But primary brain tumors had not been associated with the syndrome before.

The team went on to analyze samples from 47 patients with rhabdoid meningiomas as well as 265 additional meningiomas of diverse subtypes and grades. None of the non-rhabdoid meningiomas had a loss of BAP1. However, five of the 47 patients with rhabdoid meningiomas did have mutations or deletions affecting BAP1. These patients had poor clinical outcomes: two died of the disease and two had multiple cases of recurrence; clinical follow-up information was not available for the fifth. For those patients with intact BAP1, average time of disease progression was 116 months; for the patients with BAP1 mutations, it was only 26 months.

The presence or absence of BAP1 can be monitored with a simple and inexpensive test known as immunohistochemistry – in which a tissue sample is collected and stained for a particular protein. This approach is currently in routine use for characterizing samples of an eye cancer known as uveal melanoma and a tumor that arises from the linings of the chest and abdomen known as mesothelioma – forms of cancer tied to the tumor predisposition syndrome.

The number of cases of rhabdoid meningioma studied in this work was small; larger studies will be needed to determine the prevalence of BAP1 mutations in rhabdoid meningiomas and to assess the impact of their detection on clinical care. However, the new work strongly suggests that a careful assessment of family history is a critical for patients who develop rhabdoid meningiomas and that patients with BAP1 negative tumors may warrant more careful observation and focused care.

“Testing for BAP1 in rhabdoid meningiomas could be performed routinely and at a low cost, with the potential to change the course of clinical care and avoid overtreatment or to identify those who may need more aggressive therapy,” said Santagata. “We hope that this new work will offer insights for clinicians and patients alike as they seek more information on these tumors.”

Citation:Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas”.
Ganesh M. Shankar, Malak Abedalthagafi, Rachael A. Vaubel, Parker H. Merrill, Naema Nayyar, Corey M. Gill, Ryan Brewster, Wenya Linda Bi, Pankaj K. Agarwalla, Aaron R. Thorner, David A. Reardon, Ossama Al-Mefty, Patrick Y. Wen, Brian M. Alexander, Paul van Hummelen, Tracy T. Batchelor, Keith L. Ligon, Azra H. Ligon, Matthew Meyerson, Ian F. Dunn, Rameen Beroukhim, David N. Louis, Arie Perry, Scott L. Carter, Caterina Giannini, William T. Curry Jr, Daniel P. Cahill, Frederick G. Barker II, Priscilla K. Brastianos and Sandro Santagata. Neuro-Oncology. 2016 pp: now235
Research funding: Brain Science Foundation, Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research, King Abdulaziz City for Science and Technology Saudi Arabia, Ludwig Center at Harvard, National Institutes of Health, Susan G. Komen
Adapted from press release by Brigham and Women’s Hospital.

Gene causing sensorineural hearing loss identified

A causative gene for a highly common type of hearing loss (sensorineural hearing loss, or SNHL) has been identified by a group of Japanese researchers, who successfully replicated the condition using a transgenic mouse. This discovery could potentially be used to develop new treatments for hearing loss. The findings were published on October 5 in the online version of EMBO Molecular Medicine.

The research group included Associate Professor Takehiko Ueyama (Kobe University Biosignal Research Center, Japan) and Research Fellow Shin-ichiro Kitajiri
(Kyoto University Department of Otolaryngology, Head and Neck Surgery, Japan).

One infant in every 1000 is diagnosed with sensorineural hearing loss (1), making it an extremely common hereditary disease. (For comparison, congenital hypothyroidism is also screened for at birth and affects one in every 3000-5000 Japanese people.) It is also estimated that 25-40% of over-65s suffer from acquired sensorineural hearing loss (commonly known as age-related hearing loss), amounting to as many as 10-15 million Japanese people.

Despite this, treatment development for sensorineural hearing loss is not making progress. This is because the inner ear is a delicate and complex sensory organ that is difficult to research in vitro (outside a living organism). Currently there is no basic cure, and using a hearing aid is still the most effective treatment.

In previous research, scientists discovered about 100 causative genes for sensorineural hearing loss. However, there are many unexplained aspects to the process, such as the type of mutation occurring in these genes, and how this causes hearing impairment. This time the research team identified the causative gene for autosomal dominant nonsyndromic sensorineural deafness, DFNA1. The causative gene for this disease was first suggested in 1997, but doubts were cast regarding its universality and properties.

The research group carried out exon analysis using next generation sequencing (2,3), targeting 1120 Japanese patients suffering from hearing impairments of unknown causes. In two families they discovered a novel mutation in the genetic make-up of DIA1 molecule (DIAPH1), which is involved in the lengthening of linear actin filaments (4). These filaments play an important function in the formation and maintenance of auditory hair and inner ear hair cells. The researchers used biochemical and biological analysis methods on a molecular level to prove that the DIA1 mutant protein created by the mutation is an active form variant that lengthens actin filaments even without external stimulation.

The team also engineered a transgenic mouse that manifests this DIA1 mutant protein. They confirmed that the mouse exhibits traits of sensorineural hearing loss, saying that it “demonstrated progressive deafness, starting in the upper registers when young, and advancing with age until it covered all registers”.

Surprisingly, roughly one third of the causative genes for sensorineural hearing loss discovered so far are genes that encode proteins with functions related to actin, just like the gene identified this time. This means that as many as one third of sensorineural hearing loss cases are related to actin. By using the model transgenic mouse to find the compounds that transform actin functions within the inner ear hair cells, scientists could potentially develop new treatment for other strains of hereditary sensorineural hearing loss in addition to DFNA1. The hearing-impaired mouse could also be a key to discovering treatment for acquired sensorineural hearing loss.

Press release by Kobe University