ja_mageia

The following is a digest of some of the papers published in August and September relating to neurofibromatosis. For full abstracts, and more information on these papers please visit http://www.ncbi.nlm.nih.gov/pubmed/

Two Children’s Tumor Foundation Consensus Recommendations Papers Published

It has been a big summer for the Foundation seeing the publication of two consensus papers emerging from Foundation-sponsored workshops. Firstly, consensus recommendations for NF2 clinical trials appeared in Clinical Cancer Research authored by Evans et al. The genesis of this paper was a lunchtime brainstorming session at the 2007 NF Conference followed by a Foundation-convened two-day landmark NF2 Workshop held in New York in October 2007.  Some remarkable progress has already resulted from this initiative with three of the candidate NF2 drugs prioritized in the paper now in clinical testing. Secondly, the Foundation’s consensus recommendations for the clinical management of NF1 –related skeletal abnormalities, and looks ahead to therapeutic treatment options for these. These recommendations are the result of a February 2008 Workshop. This report was accepted for publication in the American Journal of Medical Genetics, and in addition an image from the paper was selected for the cover of the September 16, 2009 issue of AJMG, a great honor for any scientific paper.

NF1 Biology and Drug Targets

Why do tumors become resistant to drug therapies? Why do some cancer patients respond to a drug while others do not?  Light is shed on this issue by Lauchle et al.  In a team that includes Children’s Tumor Foundation NF Preclinical Consortium researchers Dr. Jennifer Lauchle and Dr. Kevin Shannon, as well as former Foundation Young Investigator Awardee Ernesto Diaz-Flores. The team created mouse models of leukemia based on Nf1 gene deficiency leukemia, and also based on the addition of ‘cooperating mutations’. In these mice as leukemia developed the tumor cells were genetically labelled and tracked. By treating and studying the different mouse models with MEK inhibitors the team found that drug resistance developed and that this was due to specific cell clones growing and become established prior to the time of drug treatment. The team also identified some candidate ‘drug resistance genes’ that included increased levels of gene RasGRP1 levels and reduced levels of p38 kinase activity in cells resistant to MEK inhibitors.This novel approach provides a strategy for understanding how drug resistance develops and for unraveling the genes involved, and hopefully paves the way to understanding, potentially predicting and treating tumors as effectively as possible.

Because the NF1 gene encodes a RAS-GTPase activating protein it has been proposed that NF1 deficiency is functionally equivalent to an oncogenic RAS. However it hasn’t been clear if the two are redundant. Cutts et al. show that the simultaneous inactivation of Nf1 and expression of K-RAS(G12D) in mouse hematopoietic cells results in AML that is fatal in primary mice within four weeks and transplantable to sublethally irradiated secondary recipients suggesting a strong cooperation rather than redundancy between Nf1 deficiency and oncogenic K-RAS.

Lin et al. reported the development of a new genetic mouse model of NF1-associated gastrointestinal stromal tumors (GIST), a manifestation of NF1 that is not well understood. The mice lack Nf1 gene function in gastric fibroblasts, and replicate features of human GIST, including increased cell proliferation and apoptosis in the gastric epithelia. Hyper-activation of both the ERK and STAT3 pathways in the gastric epithelium appear to be implicated and might represent future drug targets for treatment of these tumors.  

Gomez-Sanchez et al. overexpressed neuregulin isoform, type III-beta3 in mice and found it stimulated Schwann cell proliferation and dramatically enlarged peripheral nerves and ganglia-which come to resemble plexiform neurofibromas-but have no effect on myelin thickness. Other altered featured include the organization of Remak bundles. Schwann cell hyperproliferation and Remak bundle degeneration are early hallmarks of NF1 therefore sustained activation of the neuregulin pathway in Remak bundles may contribute to neurofibroma development.

Riccardi considered the role of the NF1 gene in normal tissue formation, maintenance, and repair. He highlighted the fact that as well as being a tumor suppressor gene NF1 is also a ‘histogenesis control gene’ that plays a key role in tissue maintenance and wound healing. 

What drives progression from benign to malignant tumors? Cabibi et al. addressed this question by examining 39 malignant peripheral nerve sheath tumors (MPNST) from patients with and without NF1. Overall the marker CD10 appears to be associated with malignancy and may be a useful marker in histological analysis. 

Nasir-ud-Din et al. described an in silico study of neurofibromin post-translational modification and highlighted a possible role for phosphorylation and O-GlcNAc in controlling the Ras signaling pathway.

NF2 Biology and Drug Targets

Recent and past Foundation Young Investigator Awardees Okay Saydam, Yiping Shen and Marianne James coauthored a study defining a miRNA profile for meningiomas, which are commonly seen in NF2. By elevating levels of miR-200a, meningioma cell growth in culture was inhibited and this is associated with decreased expression of transcription factors, ZEB1 and SIP1, and increased expression of E-cadherin, an adhesion protein associated with cell differentiation. Conversely down-regulation of miR-200a in meningiomas and arachnoidal cells resulted in increased expression of beta-catenin and cyclin D1 involved in cell proliferation. miR-200a directly targets beta-catenin mRNA, thereby inhibiting its translation and blocking beta-catenin-Wnt signaling, frequently involved in cancer. This reveals a previously unrecognized signaling cascade involved in meningioma tumor development and highlights a novel molecular interaction between miR-200a and Wnt signaling, thereby providing insights into novel therapies for meningiomas.

NF2 Clinical Diagnosis and Management

Slattery and colleagues (Fisher et al.) provided an update on the status of the NF2 natural history consortium the goal of which was to examine the relationship between the amount of change in tumor diameter and associated hearing in bilateral vestibular schwannomas (VS) in NF2. 52 patients with untreated VS were enrolled for evaluation at least twice, one year apart, via MRI and audiology exam. Overall, the VSs demonstrated significant average growth, and hearing worsened significantly over 1 year. However VS size changes were not associated with the corresponding hearing changes. Furthermore within a patient one VS cannot be used to predict changes in the contralateral VS. 

Ito et al. retrospectively reviewed data over 86 months from 27 NF2 patients and 54 patients with sporadic VS to identify factors predicting further growth of bilateral VS. Though tumor growth does seem to be greater when tumors are diagnosed at an early age, they were unable to identify factors predictive of growth and recommended close follow up be mandated for NF2 patients.

NF1 Clinical Diagnosis and Management

The NF1 phenotype appears to be more severe in patients with NF1 microdeletions than in patients with NF1 single point mutations. Pasmant et al. reported a new method for detecting and characterizing NF1 microdeletions based on a custom high-resolution oligonucleotide array comparative genomic hybridization comprising 14,207 oligonucleotide probes spanning Chromosome 17. This was able to unambiguously differentiate between the three types of microdeletions (type I, type II, and atypical) and to characterize atypical microdeletions. Further comparative studies of patients with well-characterized genotypes and phenotypes will help determine whether haploinsufficiency of deleted genes and/or genes rearrangements influence clinical outcome.

Brems et al. described glomus tumors in 11 patients with NF1. These are small, benign but painful tumors originating from the glomus body, a thermoregulatory shunt concentrated in the fingers and toes. Genetic analysis showed germ line and sporadic NF1 mutations in seven tumors and Ras-MAPK signaling was elevated in cells cultured from the germline but not somatic tumors. Neurofibromin function appears crucial in the pathogenesis of NF1 glomus tumors and the authors propose glomus tumors of the fingers or toes should be considered as part of the tumor spectrum of NF1.

Nunley et al. reviewed the predictive value of café au lait spots in NF1.  The group examined 110 patients over 3 years diagnosed with NF1 at a single NF1 subspecialty clinic, presenting with café au lait markings but no other feature of NF1. The study concluded that the majority of patients with 6 or more café au lait markings will eventually meet diagnostic criteria for NF1, typically by age 6 years, and this likelihood increases with increasing number and typical morphologic appearance of the markings.

Rea et al. examine the clinical diagnosis and management of a serious but under-recognized manifestation of NF1, cerebrovascular abnormalities. 266 NF1 patients presenting at the Hospital for Sick Children in Toronto between 1990 and 2007 with confirmed NF1 diagnosis and neuroimaging results were included. The prevalence of cerebral arteriopathy in children with NF1 in this study was at least 6% and was associated with young age and optic glioma. Arteriopathy causes stroke with resultant neurologic deficits. Medical and/or surgical interventions may prevent these complications. The group suggests that the addition of vascular imaging (MRA/conventional angiography) to brain imaging studies for early detection of arteriopathy should be considered for children with NF1, particularly young patients with optic glioma.

Visnapuu et al. examined dental health in 110 patients with NF1. Interestingly NF1 patients presented lower rate of caries compared to controls in age groups under 35 years. The difference between NF1 patients and the controls diminished by age. NF1 per se does not appear to predispose to caries; this conflicts with the existing anecdotal perception that the rate of caries may be higher in NF1 compared to reference population.

Clinical Cases

Rhabdomyosarcomas arising in various tissues associated with NF1 have been sporadically described in children and young adults. Choi et al. report a unique case of primary pulmonary rhabdomyosarcoma in an adult with NF1 for which the patient received chemotherapy without adjuvant radiation therapy as per standard pediatric protocol.

Chowdhry et al. examined eight patients of 2900 with a primary malignant bone tumor who had coexisting NF1. This was a much higher incidence than would be expected by chance. Two patients subsequently developed a second bone sarcoma, one of which was radiation induced. Four of the primary tumors were osteosarcomas, four were spindle-cell sarcomas and one a Ewing's sarcoma. All the patients were treated with chemotherapy and surgery: six of the eight appear to be cured. This study suggests a possible relationship between NF1 and the development of a bone sarcoma, the increased risk being estimated at eight times that of the normal population. 

Fauth et al. reported on two unrelated male patients in whom NF1 was not suspected until the patients presented with MPNST in their thirties and forties, respectively. Dermal features in both patients were mild, therefore both patients were considered as cases of spinal neurofibromatosis. Novel NF1 mutations identified (splice mutation) in one patient and two alterations seen in the other patient support the idea that spinal neurofibromatosis may be related to mutations with possible residual functionality. MPNSTs from both patients showed LOH affecting chromosome 17 including the NF1 locus. Furthermore, a truncating TP53 mutation was identified in the tumour of patient A. Both alterations are frequent findings in NF1-associated MPNSTs. These were proposed to be the first MPNST patients with a clinical diagnosis of spinal neurofibromatosis and suggest an unrecognized latent risk of malignancy in spinal neurofibromatosis.  Etemadifar et al. published a small but intriguing study in which both NF1 and multiple sclerosis were clinically diagnosed in seven patients in Iran. Six of the patients were women, and all had the initial diagnosis of NF1, with MS being diagnosed later in life. Ogasawara et al. identified a rare gastric schwannoma they had an NF2 mutation.

Papers Cited

Brems H, Park C, Maertens O, Pemov A, Messia L, Upadhyaya M, Claes K, Beert E, Peeters K, Mautner V, Sloan JL, Yao L, Lee CC, Sciot R, De Smet L, Legius E, Stewart DR. (2009) Glomus Tumors in Neurofibromatosis Type 1: Genetic, Functional, and Clinical Evidence of a Novel Association. Cancer Res. 2009 Sep 8. [Epub ahead of print]

Cabibi D, Zerilli M, Caradonna G, Schillaci L, Belmonte B, Rodolico V. (2009) Diagnostic and prognostic value of CD10 in peripheral nerve sheath tumors. Anticancer Res. Aug;29(8):3149-55.

Chowdhry M, Hughes C, Grimer RJ, Sumathi V, Wilson S, Jeys L. (2009) Bone sarcomas arising in patients with neurofibromatosis type 1. J Bone Joint Surg Br. 2009 Sep;91(9):1223-6.

Cutts BA, Sjogren AK, Andersson KM, Wahlstrom AM, Karlsson C, Swolin B, Bergo MO.n(2009) Nf1 deficiency co-operates with oncogenic K-RAS to induce acute myeloid leukemia in mice. Blood. Aug 26.

Elefteriou F, Kolanczyk M, Schindeler A, Viskochil DH, Hock JM, Schorry EK, Crawford AH, Friedman JM, Little D, Peltonen J, Carey JC, Feldman D, Yu X, Armstrong L, Birch P, Kendler DL, Mundlos S, Yang FC, Agiostratidou G, Hunter-Schaedle K, Stevenson DA. (2009) Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options. American Journal of Medical Genetics, Sept. 16 (epub ahead of print)

Etemadifar M, Fatehi F, Sahraian M, Borhanihaghighi A, Ardestani P, Kaji-Esfahani M, Maghzi A. (2009) Multiple sclerosis and neurofibromatosis type 1: report of seven patients from Iran. Mult Scler.  Sep;15(9):1126-30

Evans DG, Kalamarides M, Hunter-Schaedle K, Blakeley J, Allen J, Babovic-Vuskanovic D, Belzberg A, Bollag G, Chen R, DiTomaso E, Golfinos J, Harris G, Jacob A, Kalpana G, Karajannis M, Korf B, Kurzrock R, Law M, McClatchey A, Packer R, Roehm P, Rubenstein A, Slattery W 3rd, Tonsgard JH, Welling DB, Widemann B, Yohay K, Giovannini M. (2009) Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2. Clin Cancer Res. 2009 Aug 15;15(16):5032-9. Epub 2009 Aug 11.

Choi JS, Choi JS, Kim EJ. (2009) Primary pulmonary rhabdomyosarcoma in an adult with neurofibromatosis-1. Ann Thorac Surg. 2009 Oct;88(4):1356-8.

Fauth C, Kehrer-Sawatzki H, Zatkova A, Machherndl-Spandl S, Messiaen L, Amann G, Hainfellner JA, Wimmer K. (2009) Two sporadic spinal neurofibromatosis patients with malignant peripheral nerve sheath tumour. Eur J Med Genet. Aug 7.

Fisher LM, Doherty JK, Lev MH, Slattery WH. (2009) Concordance of bilateral vestibular schwannoma growth and hearing changes in neurofibromatosis 2: neurofibromatosis 2 natural history consortium. Otol Neurotol. Sep;30(6):835-41.

Gomez-Sanchez JA, Lopez de Armentia M, Lujan R, Kessaris N, Richardson WD, Cabedo H. (2009) Sustained axon-glial signaling induces Schwann cell hyperproliferation, Remak bundle myelination, and tumorigenesis. J Neurosci. 2009 Sep 9;29(36):11304-15

Ito E, Saito K, Yatsuya H, Nagatani T, Otsuka G. (2009) Factors predicting growth of vestibular schwannoma in neurofibromatosis type 2. Neurosurg Rev. Aug 12.

Lauchle JO, Kim D, Le DT, Akagi K, Crone M, Krisman K, Warner K, Bonifas JM, Li Q, Coakley KM, Diaz-Flores E, Gorman M, Przybranowski S, Tran M, Kogan SC, Roose JP, Copeland NG, Jenkins NA, Parada L, Wolff L, Sebolt-Leopold J, Shannon K. (2009) Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature. Sep 2. [Epub ahead of print]

Lin L, Chen J, Richardson JA, Parada LF. (2009) Mice lacking neurofibromin develop gastric hyperplasia. Am J Physiol Gastrointest Liver Physiol. Aug 6.

Nasir‐ud‐Din, Kaleem A, Ahmad I, Walker-Nasir E, Hoessli DC, Shakoori AR. (2009) Effect on the Ras/Raf signaling pathway of post-translational modifications of neurofibromin: In silico study of protein modification responsible for regulatory pathways. J Cell Biochem. 2009 Aug 28. [Epub ahead of print]

Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. (2009) Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol. Aug;145(8):883-7.

Ogasawara N, Sasaki M, Ishiguro H, Itoh Y, Nojiri S, Kubota E, Wada T, Kataoka H, Kuwabara Y, Joh T. (2009) Gastric schwannoma with adjacent external progression harbored aberrant NF2 gene. Dig Endosc. Jul;21(3):192-5.

Pasmant E, Sabbagh A, Masliah-Planchon J, Haddad V, Hamel MJ, Laurendeau I, Soulier J, Parfait B, Wolkenstein P, Bièche I, Vidaud M, Vidaud D. (2009) Detection and Characterization of NF1 Microdeletions by Custom High Resolution Array CGH. J Mol Diagn. 2009 Sep 18.

Rea D, Brandsema JF, Armstrong D, Parkin PC, Deveber G, Macgregor D, Logan WJ, Askalan R. (2009) Cerebral Arteriopathy in Children With Neurofibromatosis Type 1. Pediatrics. Aug 24. [Epub ahead of print]

Riccardi VM. (2009) Neurofibromatosis type 1 is a disorder of dysplasia: The importance of distinguishing features, consequences, and complications. Birth Defects Res A Clin Mol Teratol. Aug 18.

Saydam O, Shen Y, Würdinger T, Senol O, Boke E, James MF, Tannous BA, Stemmer-Rachamimov AO, Yi M, Stephens RM, Fraefel C, Gusella JF, Krichevsky AM, Breakefield XO. (2009) Down-regulated microRNA-200a in Meningiomas Promotes Tumor Growth by Reducing E-cadherin and Activating the Wnt/{beta} catenin Signaling Pathway. Mol Cell Biol. Aug 24. [Epub ahead of print]

Visnapuu V, Pienihäkkinen K, Peltonen S, Happonen RP, Peltonen J. (2009) Neurofibromatosis 1 and dental caries. Clin Oral Investig. 2009 Sep 2. [Epub ahead of print]