Malignant peripheral nerve sheath tumors in neurofibromatosis type 1: a multicenter project with 3 clinical trials

ReportA major goal of this CTDA proposal is to optimize subject recruitment in each of the clinical trials. Using the prevalence estimate for NF1 as 1 in 3,500 individuals in the population at large coupled with the cross-sectional estimate of 5% affected by MPNST, we acknowledge that few centers will have more than 2 patients with MPNST and NF1 in any given year. We anticipate 1 in 1,750,000 people will develop MPNST and NF1 on an annual basis, thus the populations of the US, Canada, and Europe will provide a maximum of 50 cases per year. Our goal is to recruit at least 2/3 of this cohort for enrollment in at least 1 of the 3 clinical trials. By developing a well-publicized network of NF1 Clinic Centers and Sarcoma Centers, we plan to offer enrollment to every individual in North America and Europe who has MPNST and NF1 into the case-control trial to identify risk factors for MPNST (clinical trial project 1). Based on inclusion and exclusion criteria, some individuals will be eligible for the clinical trial of neoadjuvant chemotherapy, and this will be offered to them as a treatment option (clinical trial project 3)

Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

cDNA sequence and genomic structure of EVI2B, a gene lying within an intron of the neurofibromatosis type 1 gene

The gene responsible for neurofibromatosis type 1 (NF1), one of the more common inherited human disorders, was identified recently, and segments of it were cloned. Two translocation breakpoints that interrupt the NF1 gene in NF1 patients flank a 60-kb segment of DNA that contains the EVI2A locus (previously reported as the EVI2 locus), the human homolog of a mouse gene, Evi-2A, implicated in retrovirus-induced murine myeloid tumors. EVI2A lies within an intron of the NF1 gene and is transcribed from telomere toward centromere, opposite to the direction of transcription of the NF1 gene. Here we describe a second locus, EVI2B, also located between the two NF1 translocation breakpoints. Full-length cDNAs from the EVI2B locus detect a 2.1-kb transcript in bone marrow, peripheral blood mononuclear cells, and fibroblasts. Sequencing studies predict an EVI2B protein of 448 amino acids that is proline-rich and contains an N-terminal signal peptide, an extracellular domain with four potential glycosylation sites, a single hydrophobic transmembrane domain, and a cytoplasmic hydrophilic domain. At the level of genomic DNA the EVI2B locus lies within the same intron of the NF1 gene as EVI2A and contains a 57-bp 5' exon that is noncoding, an 8-kb intron, and a 2078-bp 3' exon that includes the entire open reading frame. EVI2B is transcribed in the same direction as EVI2A; its 5' exon lies only 4 kb downstream from the 3' exon of the EVI2A locus. In the mouse the 5' exon of the homologous gene, Evi-2B, lies approximately 2.8 kb from the 3' end of Evi-2A, in the midst of a cluster of viral integration sites identified in retrovirus-induced myeloid tumors; thus, Evi-2B may function as an oncogene in these tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29439/1/0000521.pd

Genomic patterns of malignant peripheral nerve sheath tumor (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Purpose To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. Methods Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19(G28R) and CDK19(Y32H). Results We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). Conclusion CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.Peer reviewe

Culture-level dimensions of social axioms and their correlates across 41 cultures

Leung and colleagues have revealed a five-dimensional structure of social axioms across individuals from five cultural groups. The present research was designed to reveal the culture level factor structure of social axioms and its correlates across 41 nations. An ecological factor analysis on the 60 items of the Social Axioms Survey extracted two factors: Dynamic Externality correlates with value measures tapping collectivism, hierarchy, and conservatism and with national indices indicative of lower social development. Societal Cynicism is less strongly and broadly correlated with previous values measures or other national indices and seems to define a novel cultural syndrome. Its national correlates suggest that it taps the cognitive component of a cultural constellation labeled maleficence, a cultural syndrome associated with a general mistrust of social systems and other people. Discussion focused on the meaning of these national level factors of beliefs and on their relationships with individual level factors of belief derived from the same data set.(undefined

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.</p