Gene Summary

Gene:NF2; neurofibromin 2
Aliases: ACN, SCH, BANF
Summary:This gene encodes a protein that is similar to some members of the ERM (ezrin, radixin, moesin) family of proteins that are thought to link cytoskeletal components with proteins in the cell membrane. This gene product has been shown to interact with cell-surface proteins, proteins involved in cytoskeletal dynamics and proteins involved in regulating ion transport. This gene is expressed at high levels during embryonic development; in adults, significant expression is found in Schwann cells, meningeal cells, lens and nerve. Mutations in this gene are associated with neurofibromatosis type II which is characterized by nervous system and skin tumors and ocular abnormalities. Two predominant isoforms and a number of minor isoforms are produced by alternatively spliced transcripts. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 13 March, 2017


What does this gene/protein do?
Show (35)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer Gene Expression Regulation
  • Pyrimidines
  • Antisense RNA
  • NF2
  • Vestibulocochlear Nerve
  • Mutation
  • Magnetic Resonance Imaging
  • Adolescents
  • Genetic Predisposition
  • Sirtuin 2
  • Chromosomal Proteins, Non-Histone
  • Childhood Cancer
  • Pedigree
  • Chromosome 22
  • Differential Diagnosis
  • DNA-Binding Proteins
  • Gene Expression Profiling
  • Cell Proliferation
  • Brain Tumours
  • Immunohistochemistry
  • Spinal Cord Neoplasms
  • Meningioma
  • Skin Cancer
  • Turner Syndrome
  • Loss of Heterozygosity
  • SMARCB1 Protein
  • Neurilemmoma
  • Meningeal Neoplasms
  • Neurofibromatosis 1
  • Germ-Line Mutation
  • Base Sequence
  • Acoustic Neuroma
  • Sequence Alignment
  • Rhabdoid Tumours
  • Sensitivity and Specificity
  • Tumor Suppressor Proteins
  • Tumor Suppressor Gene
  • DNA Mutational Analysis
  • Neurofibromatosis 2
  • Brain Tumours
  • Neurofibromatosis
  • Stroke
  • Mesothelioma
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NF2 (cancer-related)

Yun CW, Yun S, Lee JH, et al.
Silencing Prion Protein in HT29 Human Colorectal Cancer Cells Enhances Anticancer Response to Fucoidan.
Anticancer Res. 2016; 36(9):4449-58 [PubMed] Related Publications
BACKGROUND: The putative functions of the cellular prion protein (PrP(c)) are believed to be associated with cell signaling, differentiation, survival, and cancer progression. With respect to cancer development and progression, elevations and mutations of PrP(c) expression have been shown to increase the risk for malignancy and metastasis in breast and colorectal cancer. Since both natural supplements and direct regulation of PrP(c) expression contribute to inhibition of cancer progression and growth, we hypothesized that knockdown of PrP(c) could lead to an enhanced synergic effect on the inhibition of cancer growth by fucoidan.
MATERIALS AND METHODS: PrP(c) expression was suppressed in HT29 human colon cancer cells by utilizing small-interfering RNA (si-PRNP), and cells were subsequently used to study the antiproliferative and anticancer effects of fucoidan treatment of HT29 human colon cancer cells.
RESULTS: Fucoidan treatment significantly inhibited growth and reduced cyclin and cyclin-dependent kinase (CDK) expression in HT29 colon cancer cells. Furthermore, silencing PrP(c) expression with si-PRNP amplified the fucoidan-induced changes in cell proliferation, apoptosis, and migration. Intraperitoneal injection of si-PRNP with fucoidan reduced proliferation and tumor volume in Balb/c nude mice. This enhanced antitumor efficacy was associated with decreased angiogenesis.
CONCLUSION: Combination of fucoidan with silencing of PrP(c) has a synergic effect on the inhibition of HT29 colon cancer cell growth. Furthermore, we provide evidence for the therapeutic application of PrP(c) silencing with other anticancer drugs for cancer.

Yuzawa S, Nishihara H, Tanaka S
Genetic landscape of meningioma.
Brain Tumor Pathol. 2016; 33(4):237-247 [PubMed] Related Publications
Meningioma is the most common intracranial tumor, arising from arachnoid cells of the meninges. Monosomy 22 and inactivating mutations of NF2 are well-known genetic alterations of meningiomas. More recently, mutations in TRAF7, AKT1, KLF4, SMO, and PIK3CA were identified by next-generation sequencing. We here reviewed 553 meningiomas for the mutational patterns of the six genes. NF2 aberration was observed in 55 % of meningiomas. Mutations of TRAF7, AKT1, KLF4, PIK3CA, and SMO were identified in 20, 9, 9, 4.5, and 3 % of cases, respectively. Altogether, 80 % of cases harbored at least one of the genetic alterations in these genes. NF2 alterations and mutations of the other genes were mutually exclusive with a few exceptions. Clinicopathologically, tumors with mutations in TRAF7/AKT1 and SMO shared specific features: they were located in the anterior fossa, median middle fossa, or anterior calvarium, and most of them were meningothelial or transitional meningiomas. TRAF7/KLF4 type meningiomas showed different characteristics in that they occurred in the lateral middle fossa and median posterior fossa as well as anterior fossa and median middle fossa, and contained a secretory meningioma component. We also discuss the mutational hotspots of these genes and other genetic/cytogenetic alterations contributing to tumorigenesis or progression of meningiomas.

Kim S, Jho EH
Merlin, a regulator of Hippo signaling, regulates Wnt/β-catenin signaling.
BMB Rep. 2016; 49(7):357-8 [PubMed] Free Access to Full Article Related Publications
Merlin, encoded by the NF2 gene, is a tumor suppressor that exerts its function via inhibiting mitogenic receptors at the plasma membrane. Although multiple mutations in Merlin have been identified in Neurofibromatosis type II (NF2) disease, its molecular mechanism is not fully understood. Here, we show that Merlin interacts with LRP6 and inhibits LRP6 phosphorylation, a critical step for the initiation of Wnt signaling. We found that treatment of Wnt3a caused phosphorylation of Merlin by PAK1, leading to detachment of Merlin from LRP6 and allowing the initiation of Wnt/β-catenin signaling. A higher level of β-catenin was found in tissues from NF2 patients. Enhanced proliferation and migration caused by knockdown of Merlin in glioblastoma cells were inhibited by suppression of β-catenin. Conclusively, these results suggest that sustained Wnt/β-catenin signaling activity induced by abrogation of Merlin-mediated inhibition of LRP6 phosphorylation might be a cause of NF2 disease. [BMB Reports 2016; 49(7): 357-358].

Radek M, Tomasik B, Wojdyn M, et al.
Neurofibromatosis type 2 (NF 2) or schwannomatosis?--Case report study and diagnostic criteria.
Neurol Neurochir Pol. 2016; 50(3):219-25 [PubMed] Related Publications
INTRODUCTION: Neurofibromatosis type 2 (NF2) and schwannomatosis are entities that may, due to the similarity of clinical symptoms, cause diagnostic difficulties. Incidence rate of both diseases is similar and estimated between 1:25,000 and 1:40,000. The genes associated with the development of the aforementioned disorders are located on chromosome 22 and lay in proxmity. Schwannomatosis is characterized by an incomplete penetrance and the risk of its transmission to the offspring is significantly lower than in the case of NF 2. Schwannomatosis clinical characteristic is similar to the NF2, however vestibular schwannomas are not present. Therefore the imaging studies evaluated by an experienced radiologist play a key role in the diagnostic process.
CASE REPORT: Forty two-year-old female hospitalized three times because of the tumors of the spinal canal was admitted to the Department of Neurosurgery and Peripheral Nerve Surgery in 2008 because of the cervical pain syndrome with concomitant headache. She was diagnosed with a schwannomatosis, recently distinguished, the third form of neurofibromatosis. MRI imaging revealed craniocervical junction tumor. Suboccipital craniectomy with concomitant C1-C2 laminectomy was done in order to remove the lesion. After the surgery the patient did not present any deficits in neurological examination and was discharged from hospital in good general condition.
CONCLUSIONS: The patient was diagnosed with schwannomatosis, recently established neurofibromatosis entity which may resemble NF2 clinically. In patients after the age of 30, in whom we observe multiple schwannomas without the concomitant hearing impairment, the diagnosis of schwannomatosis is very likely.

Ugurluer G, Chang K, Gamez ME, et al.
Genome-based Mutational Analysis by Next Generation Sequencing in Patients with Malignant Pleural and Peritoneal Mesothelioma.
Anticancer Res. 2016; 36(5):2331-8 [PubMed] Related Publications
BACKGROUND/AIM: Malignant mesothelioma is a rare malignancy with limited therapeutic options. Exome-based next-generation sequencing (NGS) techniques may direct the future of molecular targeting and improve systemic therapies for patients with mesothelioma.
MATERIALS AND METHODS: Eleven patients with NGS testing were selected, with a total of 236 somatic cancer-related mutations analyzed. Descriptive and Kaplan-Meier statistics were applied.
RESULTS: The median age was 65 years (range=27-73 years); 4 (36%) patients were females. Seven (64%) and four patients (36%) had pleural and peritoneal mesothelioma, respectively. Detectable mutations were found in 86% of the pleural and 50% of the peritoneal mesothelioma patients (overall, 73% of patients). The families of BAP1 (36%), CDKNA2A/B (27%) and NF2 (27%) represented the most frequently mutated genes. The median overall survival for all patients was 20.8 months, with 1- and 2-year survival rates of 91% and 40%, respectively.
CONCLUSION: Genomic alterations as potential therapeutic targets were found by NGS. These findings will help in the development of new screening tools and targeting therapies, and in turn impact the standard-of-care and potentially lengthen disease control and survival periods in the future.

Bueno R, Stawiski EW, Goldstein LD, et al.
Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.
Nat Genet. 2016; 48(4):407-16 [PubMed] Related Publications
We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.

Lee H, Hwang SJ, Kim HR, et al.
Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p.
Biochim Biophys Acta. 2016; 1859(4):599-611 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor derived from non-neuronal glial cells. Neurofibromatosis 2 (NF2) protein, also termed as merlin, is a well-known tumor suppressor; however, the molecular mechanism underlying this effect has not yet been fully defined. To investigate the role of NF2 in the invasiveness of GBM, we used two GBM cell lines: NF2-expressing T98G cells and NF2-deficient A172 cells. Knockdown of NF2 increased the invasiveness of T98G cells, whereas NF2-overexpressing A172 cells showed decreased invasive activity. Moreover, re-expression of NF2 reversed the high invasiveness of NF2-silenced T98G cells, indicating that NF2 negatively regulates GBM invasiveness. We further found that the NF2-mediated regulation of invasiveness was dependent on YAP and TEAD2 expression levels. NF2 also controlled the expression of YAP targets, including cysteine-rich angiogenic inducer 61 (CYR61/CCN1), by regulating the nuclear localization of YAP. Silencing of CYR61/CCN1 blocked the increased invasiveness of T98G cells, suggesting that CYR61/CCN1 is required for NF2-mediated invasiveness. Through microRNA microarray analysis, we found that NF2 negatively regulates the expression of miR-296-3p. Overexpression of miR-296-3p suppressed the expression of STAT5A, induced the phosphorylation of STAT3 by downregulating SOCS2, and increased the invasiveness of T98G cells. Taken together, we demonstrate that NF2 negatively controls the invasiveness of GBM through YAP-dependent induction of CYR61/CCN1 and miR-296-3p.

Borczuk AC, Pei J, Taub RN, et al.
Genome-wide analysis of abdominal and pleural malignant mesothelioma with DNA arrays reveals both common and distinct regions of copy number alteration.
Cancer Biol Ther. 2016; 17(3):328-35 [PubMed] Free Access to Full Article Related Publications
Malignant mesothelioma (MM) is an aggressive tumor arising from mesothelial linings of the serosal cavities. Pleural space is the most common site, accounting for about 80% of cases, while peritoneum makes up the majority of the remaining 20%. While histologically similar, tumors from these sites are epidemiologically and clinically distinct and their attribution to asbestos exposure differs. We compared DNA array-based findings from 48 epithelioid peritoneal MMs and 41 epithelioid pleural MMs to identify similarities and differences in copy number alterations (CNAs). Losses in 3p (BAP1 gene), 9p (CDKN2A) and 22q (NF2) were seen in tumors from both tumor sites, although CDKN2A and NF2 losses were seen at a higher rate in pleural disease (p<0.01). Overall, regions of copy number gain were more common in peritoneal MM, whereas losses were more common in pleural MM, with regions of loss containing known tumor suppressor genes and regions of gain encompassing genes encoding receptor tyrosine kinase pathway members. Cases with known asbestos causation (n = 32 ) were compared with those linked to radiation exposure (n = 9 ). Deletions in 6q, 14q, 17p and 22q, and gain of 17q were seen in asbestos-associated but not radiation-related cases. As reported in post-radiation sarcoma, gains outnumbered losses in radiation-associated MM. The patterns of genomic imbalances suggest overlapping and distinct molecular pathways in MM of the pleura and peritoneum, and that differences in causation (i.e., asbestos vs. radiation) may account for some of these site-dependent differences.

Li C, Cong Y, Liu X, et al.
The progress of molecular diagnostics of osteosarcoma.
Front Biosci (Landmark Ed). 2016; 21:20-30 [PubMed] Related Publications
Despite significant advances in the diagnosis and treatment of osteosarcoma in recent years, overall survival has remained low for over 2 decades. The standard diagnosis of osteosarcoma requires a combination of clinical presentation, radiologic studies, and pathologic tissue evaluation. A typical Codman's triangle in radiologic evaluation is vital in making correct diagnosis for middle or late stage of osteosarcoma. However, there is an actual demand for novel molecular markers with high sensitivity and stability for the diagnosis of early events of osteosarcoma and also the probability of recurrence and metastasis. Except that, some highly relevant gene mutations with these events could also provide valuable information regarding osteosarcoma protection. In this review, we will focus on the molecular markers which have been discovered in recent years with potential application of early stage and recurrence diagnosis and protection.

Ruggieri M, Praticò AD, Evans DG
Diagnosis, Management, and New Therapeutic Options in Childhood Neurofibromatosis Type 2 and Related Forms.
Semin Pediatr Neurol. 2015; 22(4):240-58 [PubMed] Related Publications
Neurofibromatosis type 2 (NF2; MIM # 101000) is an autosomal dominant disorder characterized by the development of vestibular schwannomas (VSs); schwannomas of other cranial, spinal, and cutaneous nerves; cranial and spinal meningiomas or other central nervous system tumors (eg, ependymomas and astrocytomas) or both. Additional features include eye (eg, early onset cataracts, optic nerve sheath meningiomas, retinal or pigment epithelial hamartomas or both, and epithelial retinal membranes) and skin abnormalities (eg, flat dermal [NF2 plaques] or spherical subcutaneous nodular schwannomas or both, and few, atypical café-au-lait spots). Clinically, children with NF2 fall into 2 main groups: (1) congenital NF2 with bilateral VSs detected as early as the first days to months of life, which can be stable or asymptomatic for 1-2 decades and suddenly progress; and (2) severe prepubertal (Wishart type) NF2 with multiple (and rapidly progressive) central nervous system tumors other-than-VS, which usually presents first, years before VSs, both associated with more marked skin and eye involvement (vs the classical mild adult [Gardner type] NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature). Individuals manifesting unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localized to a part of the peripheral nervous system have mosaic or segmental NF2; individuals developing multiple nonVS, nonintradermal cranial, spinal, and peripheral schwannomas (histologically proven) have schwannomatosis (SWNTS). NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin proteins; mosaic or segmental NF2 is because of mosaic phenomena for the NF2 gene, whereas SWNTS is caused by germline and possibly mosaic mutations either in the SMARCB1 gene (SWNTS1; MIM # 162091) or the LZTR1 gene (SWNTS2; MIM # 615670), both falling within the 22q region. Data driven from in vitro and animal studies on the merlin pathway allowed biologically targeted treatment strategies (employing Lapatinib, Erlotinib, Everolimus, Picropodophyllin, OSU.03012, Imatinib, Sorafenib, and Bevacizumab) aimed at multiple tumor shrinkage or regression or both and tumor arrest of progression with functional improvement.

Evans DG
Neurofibromatosis type 2.
Handb Clin Neurol. 2015; 132:87-96 [PubMed] Related Publications
Type 2 neurofibromatosis (NF2) is an autosomal dominant disorder caused by mutations in the NF2 tumor suppressor gene NF2 on chromosome 22. Around 1 in 33000 people are born with an NF2 mutation although more than one-third of the 60% of de novo cases are not conceived with the mutation but this develops later in embryogenesis (mosaics). NF2 has a substantial effect on life expectancy and individuals with a constitutional truncating mutation have the worst prognosis. The vast majority of people with NF2 will develop bilateral vestibular schwannomas with many developing schwannomas on other cranial, spinal and peripheral nerves. Cranial and spinal meningiomas and intraspinal low grade indolent ependymomas are the other major tumor features. Cutaneous features can be subtle with only 70% having evidence of intracutaneous plaque-like schwannomas or subcutaneous lesions on peripheral nerves. Café-au-lait patches are more frequent than in the general population but in only around 1% will meet NIH criteria for NF1.

Bhatla T, Dandekar S, Lu BY, et al.
Genomic Characterization of Poorly Differentiated Neuroendocrine Carcinoma in a Pediatric Patient.
J Pediatr Hematol Oncol. 2016; 38(1):e21-5 [PubMed] Free Access to Full Article Related Publications
Primary neuroendocrine carcinomas (NEC) are rare tumors in children and young adults, resulting in a lack of standardized treatment approach. To refine the molecular taxonomy of these rare tumors, we performed whole exome sequencing in a pediatric patient with mediastinal NEC. We identified a somatic mutation in HRAS gene and LOH regions in NF2, MYO18B, and RUX3 genes. In addition, a germline heterozygous somatic variant in BRCA2 with LOH at that same position in the tumor tissue was also found. Our data provide valuable insight into the genomic landscape of this tumor, prompting further investigation of therapeutic targets.

Hilton DA, Shivane A, Kirk L, et al.
Activation of multiple growth factor signalling pathways is frequent in meningiomas.
Neuropathology. 2016; 36(3):250-61 [PubMed] Related Publications
A minority of meningiomas are difficult to treat with surgery or radiotherapy, and chemotherapeutic alternatives are limited. This study aims to better understand pathways that are active in meningiomas, in order to direct future treatment strategies. We investigated the expression and activation of multiple growth factor receptors, their ligands and downstream signalling pathways in 30 meningiomas using immunohistochemistry. Expression was correlated with chromosome 22q loss. Membrane expression of VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR)β was seen in 83% of tumors, Axl in 70%, EGFR in 50% and insulin-like growth factor receptor in 47%. Expression was similar in low- and high-grade tumors, but membrane EGFR expression was not seen in tumors showing chromosome 22q loss (P < 0.05). Expression of ligands (IGF, NRG, VEGF, Gas 6), and signalling proteins (Mek, Erk, Jnk, Akt) and pS6RP, was widespread. Western blot confirmed widespread Axl expression and supported selective expression of EGFR in NF2-intact meningiomas. The majority of meningiomas express and show activation of multiple growth factor receptors and their signalling pathways, irrespective of tumor grade. In addition to previously reported receptors, Axl offers a new therapeutic target. The findings also suggest that anti-EGFR based therapies may be less effective in meningiomas with 22q loss.

Temiz NA, Moriarity BS, Wolf NK, et al.
RNA sequencing of Sleeping Beauty transposon-induced tumors detects transposon-RNA fusions in forward genetic cancer screens.
Genome Res. 2016; 26(1):119-29 [PubMed] Free Access to Full Article Related Publications
Forward genetic screens using Sleeping Beauty (SB)-mobilized T2/Onc transposons have been used to identify common insertion sites (CISs) associated with tumor formation. Recurrent sites of transposon insertion are commonly identified using ligation-mediated PCR (LM-PCR). Here, we use RNA sequencing (RNA-seq) data to directly identify transcriptional events mediated by T2/Onc. Surprisingly, the majority (∼80%) of LM-PCR identified junction fragments do not lead to observable changes in RNA transcripts. However, in CIS regions, direct transcriptional effects of transposon insertions are observed. We developed an automated method to systematically identify T2/Onc-genome RNA fusion sequences in RNA-seq data. RNA fusion-based CISs were identified corresponding to both DNA-based CISs (Cdkn2a, Mycl1, Nf2, Pten, Sema6d, and Rere) and additional regions strongly associated with cancer that were not observed by LM-PCR (Myc, Akt1, Pth, Csf1r, Fgfr2, Wisp1, Map3k5, and Map4k3). In addition to calculating recurrent CISs, we also present complementary methods to identify potential driver events via determination of strongly supported fusions and fusions with large transcript level changes in the absence of multitumor recurrence. These methods independently identify CIS regions and also point to cancer-associated genes like Braf. We anticipate RNA-seq analyses of tumors from forward genetic screens will become an efficient tool to identify causal events.

Kansal R, Li X, Shen J, et al.
An infant with MLH3 variants, FOXG1-duplication and multiple, benign cranial and spinal tumors: A clinical exome sequencing study.
Genes Chromosomes Cancer. 2016; 55(2):131-42 [PubMed] Related Publications
A 4-month-old male infant presented with severe developmental delay, cerebellar, brainstem, and cutaneous hemangiomas, bilateral tumors (vestibular, hypoglossal, cervical, and lumbar spinal), and few café-au-lait macules. Cerebellar and lumbar tumor biopsies revealed venous telangiectasia and intraneural perineuroma, respectively. Sequencing NF1, NF2, and RASA1 (blood), and NF2 and SMARCB1 (lumbar biopsy) was negative for pathogenic mutations. Clinical exome sequencing (CES), requested for tumor syndrome diagnosis, revealed two heterozygous missense variants, c.359T>C;p.Phe120Ser and c.3344G>A;p.Arg1115Gln, in MLH3 (NM_001040108.1), a DNA mismatch repair (MMR) gene, Polyphen-predicted as probably damaging, and benign, respectively. Sanger sequencing confirmed both variants in the proband, and their absence in the mother; biological father unavailable. Both biopsied tissues were negative for microsatellite instability, and expressed MLH1, MSH2, PMS2, MSH6, and MLH3 immunohistochemically. Chromosomal microarray showed a 133 kb segment copy number duplication of 14q12 region encompassing FOXG1, possibly explaining the developmental delay, but not the tumors. The presence of MLH3 variants with multiple benign neural and vascular tumors was intriguing for their possible role in the pathogenesis of these neoplasms, which were suspicious for, but not diagnostic of, constitutional MMR deficiency. However, functional assays of non-neoplastic patient-derived cells showed intact base-base MMR function. Also, no previous FOXG1-aberrant patient was reported with tumors. We now report a 3-year-old FOXG1-duplicated patient with a yet undescribed tumor syndrome with clinical features of neurofibromatosis types I and II, where several validation studies could not ascertain the significance of CES findings; further studies may elucidate precise mechanisms and diagnosis for clinical management, including tumor surveillance.

Subbiah V, Wagner MJ, McGuire MF, et al.
Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine.
Oncotarget. 2015; 6(38):40642-54 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy-refractory osteosarcoma to guide molecularly targeted therapy.
PATIENTS AND METHODS: Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN's Ingenuity® Pathway Analysis.
RESULTS: In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA, c-MET, and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib. In Patient #2, aberrations included NF2 loss in exons 2-16, PDGFRα amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFRα and TP53 aberrations. Both the patients did not benefit from matched therapy.
CONCLUSIONS: Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized therapies for cancer. Methods for such profiling are evolving and need to be refined to better assist clinicians in making treatment decisions based on the large amount of data that results from this type of testing. Further research in this area is warranted.

Quan M, Cui J, Xia T, et al.
Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling.
Cancer Res. 2015; 75(22):4778-89 [PubMed] Free Access to Full Article Related Publications
Merlin, the protein encoded by the NF2 gene, is a member of the band 4.1 family of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer.

Ozluk Y, Taheri D, Matoso A, et al.
Renal carcinoma associated with a novel succinate dehydrogenase A mutation: a case report and review of literature of a rare subtype of renal carcinoma.
Hum Pathol. 2015; 46(12):1951-5 [PubMed] Related Publications
Renal cell carcinoma (RCC) linked to germline mutation of succinate dehydrogenase subunits A, B, C, and D (SDHA, SDHB, SDHC, and SDHD, respectively) has been recently included as a provisional entity in the 2013 International Society of Urological Pathology Vancouver classification. Most SDH-deficient tumors show SDHB mutation, with only a small number of RCC with SDHC or SDHD having been reported to date. Only one case of SDH-deficient renal carcinoma known to be SDHA mutated has been previously reported. Here we report an additional RCC harboring an SDHA mutation occurring in a 62-year-old man with right flank pain and nodal metastasis. The tumor was characterized by an infiltrative pattern with solid, acinar, and papillary components. Loss of SDHA and SDHB protein by immunohistochemistry confirmed the diagnosis. Hybrid capture-based comprehensive genomic profiling identified 3 genomic alterations in tumor tissue: (i) a novel single-nucleotide splice site deletion in SDHA gene, (ii) single-nucleotide deletion in NF2 gene, and (iii) EGFR gene amplification of 19 copies. This is the second report of SDHA-mutated RCC. With increased awareness, this rare tumor can be recognized on the basis of distinctive morphology and confirmation by immunohistochemistry and genomic profiling.

Mäki-Nevala S, Sarhadi VK, Knuuttila A, et al.
Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing.
Lung. 2016; 194(1):125-35 [PubMed] Related Publications
BACKGROUND: Asbestos is a carcinogen linked to malignant mesothelioma (MM) and lung cancer. Some gene aberrations related to asbestos exposure are recognized, but many associated mutations remain obscure. We performed exome sequencing to determine the association of previously known mutations (driver gene mutations) with asbestos and to identify novel mutations related to asbestos exposure in lung adenocarcinoma (LAC) and MM.
METHODS: Exome sequencing was performed on DNA from 47 tumor tissues of MM (21) and LAC (26) patients, 27 of whom had been asbestos-exposed (18 MM, 9 LAC). In addition, 9 normal lung/blood samples of LAC were sequenced. Novel mutations identified from exome data were validated by amplicon-based deep sequencing. Driver gene mutations in BRAF, EGFR, ERBB2, HRAS, KRAS, MET, NRAS, PIK3CA, STK11, and ephrin receptor genes (EPHA1-8, 10 and EPHB1-4, 6) were studied for both LAC and MM, and in BAP1, CUL1, CDKN2A, and NF2 for MM.
RESULTS: In asbestos-exposed MM patients, previously non-described NF2 frameshift mutation (one) and BAP1 mutations (four) were detected. Exome data mining revealed some genes potentially associated with asbestos exposure, such as MRPL1 and SDK1. BAP1 and COPG1 mutations were seen exclusively in MM. Pathogenic KRAS mutations were common in LAC patients (42 %), both in non-exposed (n = 5) and exposed patients (n = 6). Pathogenic BRAF mutations were found in two LACs.
CONCLUSION: BAP1 mutations occurred in asbestos-exposed MM. MRPL1, SDK1, SEMA5B, and INPP4A could possibly serve as candidate genes for alterations associated with asbestos exposure. KRAS mutations in LAC were not associated with asbestos exposure.

Wang Z, Kong QT, Wu XH, Zhu XX
Long-term survival in gliosarcoma with radiation-induced meningeal sarcomas: Case report and molecular features.
J Cancer Res Ther. 2015 Jul-Sep; 11(3):651 [PubMed] Related Publications
Gliosarcoma is a rare primary malignant tumor of the central nervous system with poor prognosis. The median survival time of this disease ranges from 6 months to 14.8 months. However, a computer literature search indicated few long-term survivors. We investigated a case of a survivor of gliosarcoma with radiation-induced meningeal sarcomas, who showed no indication of recurrence for more than 9 years. A battery of molecular studies was performed to develop a molecular profile of this unique patient. We also reviewed the distinct clinical and molecular features of the tumor.

Luo ZL, Cheng SQ, Shi J, et al.
A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma.
Nat Commun. 2015; 6:8457 [PubMed] Free Access to Full Article Related Publications
Merlin, which is encoded by the tumour suppressor gene Nf2, plays a crucial role in tumorigenesis and metastasis. However, little is known about the functional importance of Merlin splicing forms. In this study, we show that Merlin is present at low levels in human hepatocellular carcinoma (HCC), particularly in metastatic tumours, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 ((Δ2-4)Merlin) is amplified in HCC and portal vein tumour thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that (Δ2-4)Merlin interferes with the capacity of wild-type Merlin to bind β-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, (Δ2-4)Merlin overexpression increases the expression levels of β-catenin and stemness-related genes, induces the epithelium-mesenchymal-transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the (Δ2-4)Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis.

Peyre M, Salaud C, Clermont-Taranchon E, et al.
PDGF activation in PGDS-positive arachnoid cells induces meningioma formation in mice promoting tumor progression in combination with Nf2 and Cdkn2ab loss.
Oncotarget. 2015; 6(32):32713-22 [PubMed] Free Access to Full Article Related Publications
The role of PDGF-B and its receptor in meningeal tumorigenesis is not clear. We investigated the role of PDGF-B in mouse meningioma development by generating autocrine stimulation of the arachnoid through the platelet-derived growth factor receptor (PDGFR) using the RCAStv-a system. To specifically target arachnoid cells, the cells of origin of meningioma, we generated the PGDStv-a mouse (Prostaglandin D synthase). Forced expression of PDGF-B in arachnoid cells in vivo induced the formation of Grade I meningiomas in 27% of mice by 8 months of age. In vitro, PDGF-B overexpression in PGDS-positive arachnoid cells lead to increased proliferation.We found a correlation of PDGFR-B expression and NF2 inactivation in a cohort of human meningiomas, and we showed that, in mice, Nf2 loss and PDGF over-expression in arachnoid cells induced meningioma malignant transformation, with 40% of Grade II meningiomas. In these mice, additional loss of Cdkn2ab resulted in a higher incidence of malignant meningiomas with 60% of Grade II and 30% of Grade III meningiomas. These data suggest that chronic autocrine PDGF signaling can promote proliferation of arachnoid cells and is potentially sufficient to induce meningiomagenesis. Loss of Nf2 and Cdkn2ab have synergistic effects with PDGF-B overexpression promoting meningioma malignant transformation.

Gossai N, Biegel JA, Messiaen L, et al.
Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis.
Am J Med Genet A. 2015; 167A(12):3186-91 [PubMed] Related Publications
We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CSS), and schwannomatosis. CSS is a rare congenital syndrome with characteristic clinical findings. This thirty-three-year-old man was diagnosed early in life with the constellation of moderate intellectual disability, hypotonia, mild microcephaly, coarse facies, wide mouth with full lips, hypoplasia of the digits, and general hirsutism. At age 26, he was found to have schwannomatosis after presenting with acute spinal cord compression. Blood and tissue analysis of multiple subsequent schwannoma resections revealed a germline missense mutation of SMARCB1, acquired loss of 22q including SMARCB1 and NF2 and mutation of the remaining NF2 wild-type allele-thus completing the four-hit, three-event mechanism associated with schwannomatosis. Variations in five genes have been associated with the Coffin-Siris phenotype: ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1. Of these genes, SMARCB1 has a well-established association with schwannomatosis and malignancy. This is the first report of a patient with a constitutional missense mutation of SMARCB1 resulting in CSS and subsequent development of schwannomatosis. This finding demonstrates that a SMARCB1 mutation may be the initial "hit" (constitutional) for a genetic disorder with subsequent risk of developing schwannomas and other malignancies, and raises the possibility that other patients with switch/sucrose non-fermenting (SWI/SNF) mutations may be at increased risk for tumors.

Oh JE, Ohta T, Satomi K, et al.
Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas.
J Neuropathol Exp Neurol. 2015; 74(10):952-9 [PubMed] Related Publications
Schwannomas are benign nerve sheath tumors composed of well-differentiated Schwann cells. Other than frequent NF2 (neurofibromatosis type 2) mutations (50%-60%), their molecular pathogenesis is not fully understood. LATS1 and LATS2 are downstream molecules of NF2 and are negative regulators of the yes-associated protein (YAP) oncogene in the Hippo signaling pathway. We assessed mutations of the NF2, LATS1, and LATS2 genes, promoter methylation of LATS1 and LATS2, and expression of YAP and phosphorylated YAP in 82 cases of sporadic schwannomas. Targeted sequencing using the Ion Torrent Proton instrument revealed NF2 mutations in 45 cases (55%), LATS1 mutations in 2 cases (2%), and LATS2 mutations in 1 case (1%) of schwannoma. Methylation-specific polymerase chain reaction showed promoter methylation of LATS1 and LATS2 in 14 cases (17%) and 25 cases (30%), respectively. Overall, 62 cases (76%) had at least 1 alteration in the NF2, LATS1, and/or LATS2 genes. Immunohistochemistry revealed nuclear YAP expression in 18 of 42 cases of schwannoma (43%) and reduced cytoplasmic phosphorylated YAP expression in 15 of 49 cases of schwannoma (31%), all of which had at least 1 alteration in the NF2, LATS1, and/or LATS2 genes. These results suggest that an abnormal Hippo signaling pathway is involved in the pathogenesis of most sporadic schwannomas.

Garcia-Rendueles ME, Ricarte-Filho JC, Untch BR, et al.
NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition.
Cancer Discov. 2015; 5(11):1178-93 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation is insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP-TEAD transcriptional program. We find that the three RAS genes are themselves YAP-TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacologic disruption of YAP-TEAD with verteporfin blocks RAS transcription and signaling and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability.
SIGNIFICANCE: Intensification of mutant RAS signaling through copy-number imbalances is commonly associated with transformation. We show that NF2/merlin inactivation augments mutant RAS signaling by promoting YAP/TEAD-driven transcription of oncogenic and wild-type RAS, resulting in greater MAPK output and increased sensitivity to MEK inhibitors.

Roma D, Palma P, Capolino R, et al.
Spinal ependymoma in a patient with Kabuki syndrome: a case report.
BMC Med Genet. 2015; 16:80 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Kabuki syndrome is a rare disorder characterized by the association of mental retardation and postnatal growth deficiency with distinctive facial appearance, skeletal anomalies, cardiac and renal malformation. Two causative genes have been identified in patients with Kabuki syndrome. Mutation of KMT2D (MLL2) was identified in 55-80% of patients, while 9-14% of KMT2D negative patients have mutation in KDM6A gene. So far, few tumors have been reported in patients with Kabuki syndrome. We describe the first case of a patient with spinal ependymoma and Kabuki syndrome.
CASE PRESENTATION: A 23 years old girl followed at our Center for KMT2D mutated Kabuki syndrome since she was 4 years old presented with acute lumbar pain and intermittent tactile hyposthenia of the feet. Spine magnetic resonance revealed a lumbar endocanalar mass. She underwent surgical resection of the lesion and histologic examination showed a tanycytic ependymoma (WHO grade II).
CONCLUSION: Kabuki syndrome is not considered a cancer predisposition syndrome. Nonetheless, a number of tumors have been reported in patients with Kabuki syndrome. Spinal ependymoma is a rare disease in the pediatric and young adult population. Whereas NF2 mutations are frequently associated to ependymoma such an association has never been described in Kabuki syndrome. To our knowledge this is the first case of ependymoma in a KMT2D mutated Kabuki syndrome patient. Despite KMT2D role in cancer has previously been described, no genetic data are available for previously reported Kabuki syndrome patients with tumors. Nonetheless, the association of two rare diseases raises the suspicion for a common determinant.

Conboy E, Dhamija R, Wang M, et al.
Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines.
J Med Genet. 2016; 53(2):123-6 [PubMed] Related Publications
BACKGROUND: Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is an autosomal-dominant disorder characterised by lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation and deafness. There is significant clinical overlap between NSML and other disorders that result from dysregulated rat sarcoma/mitogen-activated protein kinase pathway (RASopathies). Except for neurofibromatosis type 1, other RASopathies are not known to be typically associated with neurogenic tumours.
METHODS AND RESULTS: We evaluated patients from three families with pigmentary skin lesions, progressive neuropathy, enlarged nerves, massive burden of paraspinal tumours (neurofibroma was confirmed in one patient) and a clinical diagnosis of NSML. All patients had a mutation in the protein tyrosine phosphatase catalytic domain of the PTPN11 gene; two unrelated patients had the p.Thr468Met mutation, while the family consisting of two affected individuals harboured the p.Thr279Cys mutation. Molecular analysis performed on hypertrophic nerve tissue did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes.
CONCLUSIONS: Neurogenic tumours and hypertrophic neuropathy are unusual complications of NSML and may be an under-recognised manifestation that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation.

Selmansberger M, Braselmann H, Hess J, et al.
Genomic copy number analysis of Chernobyl papillary thyroid carcinoma in the Ukrainian-American Cohort.
Carcinogenesis. 2015; 36(11):1381-7 [PubMed] Free Access to Full Article Related Publications
One of the major consequences of the 1986 Chernobyl reactor accident was a dramatic increase in papillary thyroid carcinoma (PTC) incidence, predominantly in patients exposed to the radioiodine fallout at young age. The present study is the first on genomic copy number alterations (CNAs) of PTCs of the Ukrainian-American cohort (UkrAm) generated by array comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering of CNA profiles revealed a significant enrichment of a subgroup of patients with female gender, long latency (>17 years) and negative lymph node status. Further, we identified single CNAs that were significantly associated with latency, gender, radiation dose and BRAF V600E mutation status. Multivariate analysis revealed no interactions but additive effects of parameters gender, latency and dose on CNAs. The previously identified radiation-associated gain of the chromosomal bands 7q11.22-11.23 was present in 29% of cases. Moreover, comparison of our radiation-associated PTC data set with the TCGA data set on sporadic PTCs revealed altered copy numbers of the tumor driver genes NF2 and CHEK2. Further, we integrated the CNA data with transcriptomic data that were available on a subset of the herein analyzed cohort and did not find statistically significant associations between the two molecular layers. However, applying hierarchical clustering on a 'BRAF-like/RAS-like' transcriptome signature split the cases into four groups, one of which containing all BRAF-positive cases validating the signature in an independent data set.

Weissferdt A, Tang X, Suster S, et al.
Pleuropulmonary Meningothelial Proliferations: Evidence for a Common Histogenesis.
Am J Surg Pathol. 2015; 39(12):1673-8 [PubMed] Related Publications
Primary pleuropulmonary meningothelial proliferations include minute pulmonary meningothelial-like nodules (MPMN) and pleural or pulmonary meningiomas (PPM). These lesions share histologic, ultrastructural, and immunohistochemical features with meningiomas of the central nervous system (CNS). Meningiomas of the CNS exhibit a number of genetic abnormalities, most commonly loss of the neurofibromatosis (NF) 2 gene on chromosome 22. The molecular changes of pleuropulmonary meningothelial proliferations, however, have only rarely been investigated. This study explores the status of the NF2 gene in pleuropulmonary meningothelial proliferations compared with CNS meningioma using interphase fluorescence in situ hybridization. Whole tissue sections of 9 pleuropulmonary meningothelial lesions (6 MPMNs and 3 PPMs) and 9 CNS meningiomas were analyzed by fluorescence in situ hybridization using a commercially available locus-specific probe for the NF2 region. Deletion of the NF2 gene was identified in 2 MPMNs, 1 PPM, and 4 CNS meningiomas. Chromosomal gains of 22q were noted in 2 cases of MPMN and 1 PPM. Our results indicate that pleuropulmonary meningothelial lesions share common genetic pathways with CNS meningiomas. In addition, they provide support for the hypothesis that MPMN and PPM are related lesions that may arise from the same precursor cell. As for CNS meningiomas, these mutational changes may provide additional targets for future personalized therapies.

Hexter A, Jones A, Joe H, et al.
Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients.
J Med Genet. 2015; 52(10):699-705 [PubMed] Related Publications
BACKGROUND: Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype-phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown.
METHODS: We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan-Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2.
RESULTS: The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6-15 had lower mortality than patients with splice-site mutations in exons 1-5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier.
CONCLUSIONS: Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.

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