Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs(PNETs) that correlated with high level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A knockdown cells although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.

Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin dependent kinases (CDKs), commonly through loss of CDK inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor-based therapy in MPNSTs. Experimental Design:We examined patient-matched MPNSTs and precursor lesions by RNA-Seq and IHC. Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined. Tumor suppressive effects of CDK inhibitors were measured in MPNST cells and orthotopic tumors.Results: RABL6A was dramatically upregulated in human MPNSTs compared to precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G1 arrest that coincided with p27 upregulation, CDK downregulation and RB1 activation. The growth suppressive effects of RABL6A loss, and its regulation of RB1, were largely rescued by p27 depletion. Importantly, reactivation of RB1 using a CDK4/6 inhibitor (palbociclib) killed MPNST cells in vitro in a RABL6A-dependent manner and suppressed MPNST growth in vivo. Low-dose combination of drugs targeting multiple RB1 kinases (CDK4/6, CDK2) had enhanced anti-tumorigenic activity associated with potential MPNST cell redifferentiation.Conclusions: RABL6A is a new driver of MPNST pathogenesis that acts in part through p27-RB1 inactivation. Our results suggest RB1 targeted therapy with multiple pathway drugs may effectively treat MPNSTs.

Microdeletions of the long arm of chromosome 17 are being reported with increasing frequency. Deletions of 17q22q23.2 may represent a genetically recognizable phenotype although its spectrum of genomic abnormalities, clinical manifestations, and critical regions are not fully delineated. Isolated reports and small case series suggest that deletions of 17q22q23.2 result in haploinsufficiency of dosage sensitive genes NOG, TBX2, and TBX4, which may be responsible for many aspects of the phenotype. Shared clinical features in this group of patients include microcephaly, prenatal onset growth restriction, heart defects, tracheoesophageal fistula, and esophageal atresia (TEF/EA), skeletal anomalies, and moderate to severe global developmental delay. We describe a female patient who presented with severe congenital microcephaly, thyroglossal duct cyst, sensorineural hearing loss, mild tracheomalacia, abnormal auricles, pulmonary hypertension, developmental delay, and postnatal onset growth delay. She had no TEF/EA or heart defects. Using a high density oligonucleotide microarray, we identified a microdeletion at 17q22q23.2, resulting in the heterozygous loss of several genes, including TBX2 and TBX4 but not NOG. The breakpoints did not lie within known segmental duplications. This case helps to further delineate the critical region for TEF/EA, which is likely confined to the chromosomal region proximal to 17q23.1, and suggests that genes in 17q23.1q23.2 may be associated with thyroglossal duct cysts. The role of TBX2 and TBX4 in pulmonary hypertension warrants investigation.

Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease.

Seabirds are declining globally, though the threats they face differ among and within species and populations. Following substantial population declines at several breeding colonies, Leach's Storm-Petrel (Hydrobates leucorhous) was uplisted from Least Concern to Vulnerable by the International Union for Conservation of Nature (IUCN) in 2016. Reasons for these declines are unclear, and it is important to identify threats the species faces across its global breeding range to guide research directions and inform conservation efforts. We solicited feedback from 37 Leach's Storm-Petrel scientific experts from eight countries on the importance of different threats facing the species on land and at sea. Perceived threats to extant colonies varied spatially, with a consensus within regions for main threats. Most researchers agreed that the main threats at or near colonies are avian and mammalian predators and onshore light attraction. At-sea threats have been less studied and were harder to identify and rank, but include offshore lights and structures, spatial shifts in prey, and contaminants. Climate change was not listed specifically because of its multifaceted repercussions, but several perceived threats are linked to climate change. Globally, introduction of mammalian predators is an overarching driver of seabird colony decline or extirpation; thus biosecurity must be considered an important measure for the conservation of storm-petrels. In addition, filling knowledge gaps and implementing a series of regionally relevant and targeted strategies that lead to small but cumulative conservation successes may be the best approach for this species. Avis d'experts sur les menaces pesant sur les océanites cul-blanc (Hydrobates leucorhous) dans l'ensemble de leur aire de répartitionRÉSUMÉ. Les oiseaux de mer sont en déclin à l'échelle mondiale, bien que les menaces auxquelles ils sont confrontés diffèrent selon les espèces et les populations et au sein de celles-ci. Suite à une diminution significative de la population dans plusieurs colonies de reproduction, l'Océanite cul-blanc (Hydrobates leucorhous) est passée de "Préoccupation mineure" à "Vulnérable" par l'UICN en 2016. Les raisons de ces déclins ne sont pas claires et il est important d'identifier les menaces auxquelles l'espèce est confrontée dans son aire de reproduction mondiale pour guider les orientations de recherche et informer les efforts de conservation. Nous avons sollicité l'avis de 37 experts scientifiques de l'Océanite cul-blanc venant de huit pays sur l'importance des différentes menaces auxquelles l'espèce est confrontée sur terre et en mer. Les menaces perçues pour les colonies existantes varient spatialement, avec un consensus au sein des régions pour les principales menaces. La plupart des chercheurs s'accordent à dire que les principales menaces sur ou à proximité des colonies sont les prédateurs aviaires et mammifères ainsi que l'attraction de la lumière. Les menaces en mer ont été moins étudiées et étaient plus difficiles à identifier et à classer, ...