Publications by authors named "Christine A Pratilas"

59 Publications

Considerations in Methods and Timing for Delivery of Genetic Counseling Information to Pediatric Oncology Patients and Families.

J Pediatr Hematol Oncol 2021 Dec 30. Epub 2021 Dec 30.

The Johns Hopkins University Departments of Genetic Medicine Pediatrics Oncology, The Johns Hopkins University School of Medicine The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Many pediatric oncology patients and their families may benefit from genetic counseling and testing; however, identifying the best timing and delivery method for these referrals is sometimes a challenge. The goal of this study was to understand how and when caregivers prefer to receive information about genetic counseling and testing. A total of 56 surveys completed by caregivers at The Johns Hopkins Hospital Pediatric Oncology unit in Baltimore, Maryland were analyzed. A sizeable subset of respondents was interested in receiving information about the availability of genetic counseling from an oncology doctor or nurse, but not a genetic counselor (n=13/55, 24%). Most respondents preferred to be informed about genetic services at diagnosis (n=28/54, 52%) or within 1 to 2 months of diagnosis (n=14/54, 26%). In conclusion, patients and their families may benefit from prompt and early recognition of the risk of cancer predisposition syndromes, preferably within the first 2 months following diagnosis. Oncology professionals are an important source of information, and can introduce the availability of genetic counseling services and motivate families to undergo genetic testing, though alternative communication methods such as brochures may also be useful.
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http://dx.doi.org/10.1097/MPH.0000000000002376DOI Listing
December 2021

Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling.

Dis Model Mech 2022 Jan 27;15(1). Epub 2022 Jan 27.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper.
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http://dx.doi.org/10.1242/dmm.047621DOI Listing
January 2022

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF-Mutant Human Glioma.

Clin Cancer Res 2021 11 25;27(22):6197-6208. Epub 2021 Aug 25.

Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.

Purpose: Selective RAF-targeted therapy is effective in some patients with BRAF-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms.

Experimental Design: Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples ( = 15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing (RNA-seq). Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAF-mutant glioma cell lines.

Results: Analysis of 15 tissue sample pairs identified 13 alterations conferring putative resistance were identified among nine paired samples (including mutations involving , and ). We performed functional validation of mechanisms of resistance, including loss of , or , in BRAF-mutant glioma lines, and demonstrate they are capable of conferring resistance . Knockdown of CBL resulted in increased expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN) restored sensitivity to BRAFi. We identified and validated CRAF upregulation as a mechanism of resistance in one resistant sample. RNA-seq analysis identified two emergent expression patterns in resistant samples, consistent with expression patterns of known glioma subtypes.

Conclusions: Resistance mechanisms to BRAFi in glioma are varied and may predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595717PMC
November 2021

Exceptional response to the ALK and ROS1 inhibitor lorlatinib and subsequent mechanism of resistance in relapsed F1174L-mutated neuroblastoma.

Cold Spring Harb Mol Case Stud 2021 08 2;7(4). Epub 2021 Aug 2.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Division of Pediatric Oncology, Baltimore, Maryland 21287, USA.

Treatment of high-risk neuroblastoma typically incorporates multiagent chemotherapy, surgery, radiation therapy, autologous stem cell transplantation, immunotherapy, and differentiation therapy. The discovery of activating mutations in ALK receptor tyrosine kinase () in ∼8% of neuroblastomas opens the possibility of further improving outcomes for this subset of patients with the addition of ALK inhibitors. ALK inhibitors have shown efficacy in tumors such as non-small-cell lung cancer and anaplastic large cell lymphoma in which wild-type ALK overexpression is driven by translocation events. In contrast, ALK mutations driving neuroblastomas are missense mutations in the tyrosine kinase domain yielding constitutive activation and differing sensitivity to available ALK inhibitors. We describe a case of a patient with relapsed, refractory, metastatic F1174L-mutated neuroblastoma who showed no response to the first-generation ALK inhibitor crizotinib but had a subsequent complete response to the ALK/ROS1 inhibitor lorlatinib. The patient's disease relapsed after 13 mo of treatment. Sequencing of cell-free DNA at the time of relapse pointed toward a potential mechanism of acquired lorlatinib resistance: amplification of and and a Q61K mutation. We review the literature regarding differing sensitivity of mutations found in neuroblastoma to current FDA-approved ALK inhibitors and known pathways of acquired resistance. Our report adds to the literature of important correlations between neuroblastoma mutation status and clinical responsiveness to ALK inhibitors. It also highlights the importance of understanding acquired mechanisms of resistance.
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http://dx.doi.org/10.1101/mcs.a006064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327881PMC
August 2021

Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes.

J Immunother Cancer 2021 05;9(5)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Background: Current therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy.

Methods: 66 osteosarcoma tissue specimens were analyzed by immunohistochemistry (IHC) and immune markers were digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional cytometry. Comparative transcriptomic studies of distinct tumor-normal lung 'PM interface' and 'PM interior' regions from 16 PMs were performed. Clinical follow-up (median 24 months) was available from resection.

Results: IHC revealed a statistically significantly higher concentration of TILs expressing immune checkpoint and immunoregulatory molecules in PMs compared with primary bone tumors (including programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and indoleamine 2,3-dioxygenase (IDO1). Remarkably, these lymphocytes are excluded at the PM interface compared with PM interior. TILs from PMs exhibited significantly higher amounts of PD-1 and LAG-3 and functional cytokines including interferon-γ (IFNγ) by flow cytometry. Gene expression profiling further confirmed the presence of CD8 and CD4 lymphocytes concentrated at the PM interface, along with upregulation of immunoregulatory molecules and IFNγ-driven genes in the same region. We further discovered a strong alternatively activated macrophage signature throughout the entire PMs along with a polymorphonuclear myeloid-derived suppressor cell signature focused at the PM interface. Expression of PD-L1, LAG-3, and colony-stimulating factor 1 receptor (CSF1R) at the PM interface was associated with significantly worse progression-free survival (PFS), while gene sets indicative of productive T cell immune responses (CD8 T cells, T cell survival, and major histocompatibility complex class 1 expression) were associated with significantly improved PFS.

Conclusions: Osteosarcoma PMs exhibit immune exclusion characterized by the accumulation of TILs at the PM interface. These TILs produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with patient outcomes, which could be exploited for successful immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144029PMC
May 2021

Predictors of Recurrence and Patterns of Initial Failure in Localized Ewing Sarcoma: A Contemporary 20-Year Experience.

Sarcoma 2021 17;2021:6681741. Epub 2021 Apr 17.

Department of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma.

Methods: The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence.

Results: In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size, <95% tumor necrosis following neoadjuvant chemotherapy (NAC; HR 14.3,  = 0.028) and radiological tumor size change during NAC (HR 1.04 per 1% decrease in size change,  = 0.032) were independent predictors of recurrence. Among patients experiencing distant recurrence, pulmonary metastases were present in 82% and were the only identifiable site of disease in 53%.

Conclusions: Poor pathologic or radiologic response to NAC is predictive of recurrence in patients with localized Ewing sarcoma. Suboptimal tumor size reduction following chemotherapy provides a means to risk-stratify patients who do not undergo definitive resection. Isolated pulmonary recurrence was a common event.
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http://dx.doi.org/10.1155/2021/6681741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068528PMC
April 2021

Chromosome 8 gain is associated with high-grade transformation in MPNST.

JCI Insight 2021 03 22;6(6). Epub 2021 Mar 22.

Department of Internal Medicine, Division of Oncology, Washington University in St. Louis, St. Louis, Missouri, USA.

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.
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http://dx.doi.org/10.1172/jci.insight.146351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026192PMC
March 2021

Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling.

Epigenetics Chromatin 2021 01 13;14(1). Epub 2021 Jan 13.

Center for Cancer and Cell Biology, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, USA.

Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.
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http://dx.doi.org/10.1186/s13072-020-00380-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805211PMC
January 2021

Improving Detection of Cancer Predisposition Syndromes in Pediatric Oncology.

J Pediatr Hematol Oncol 2021 08;43(6):e891-e896

Department of Pediatrics.

Implementation and adherence to consensus statement criteria for referral of pediatric cancer patients for genetic evaluation are critical to identify the 5% to 10% with a genetic cancer predisposition syndrome. The authors implemented a Plan-Do-Study-Act quality improvement initiative aimed at increasing referrals of at-risk patients. Retrospective chart review was followed by educational intervention-with impact assessed over a 9-month prospective chart review. Referral rate improved >2-fold and there was an improvement in documented oncologic history to at least a third-degree relative. The integration of quality improvement can be an effective tool to improve the referral of patients with an elevated risk for a cancer predisposition syndrome.
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http://dx.doi.org/10.1097/MPH.0000000000001987DOI Listing
August 2021

Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa138. Epub 2020 Oct 15.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.

Background: RAS effector signaling pathways such as PI3K/mTOR and ERK are frequently dysregulated in glioblastoma. While small molecule targeted therapies against these pathways have appeared promising in preclinical studies, they have been disappointing in clinical trials due to toxicity and de novo and adaptive resistance. To identify predictors of glioblastoma sensitivity to dual pathway inhibition with mTORC1/2 and MEK inhibitors, we tested these agents, alone and in combination, in a cohort of genomically characterized glioblastoma cell lines.

Methods: Seven genomically characterized, patient-derived glioblastoma neurosphere cell lines were evaluated for their sensitivity to the dual mTORC1/2 kinase inhibitor sapanisertib (MLN0128, TAK-228) alone or in combination with the MEK1/2 inhibitor trametinib (GSK1120212), using assessment of proliferation and evaluation of the downstream signaling consequences of these inhibitors.

Results: Sapanisertib inhibited cell growth in neurosphere lines, but induced apoptosis only in a subset of lines, and did not completely inhibit downstream mTOR signaling via ribosomal protein S6 (RPS6). Growth sensitivity to MEK inhibitor monotherapy was observed in a subset of lines defined by loss of NF1, was predicted by an ERK-dependent expression signature, and was associated with effective phospho-RPS6 inhibition. In these lines, combined MEK/mTOR treatment further inhibited growth and induced apoptosis. Combined MEK and mTOR inhibition also led to modest antiproliferative effects in lines with intact NF1 and insensitivity to MEK inhibitor monotherapy.

Conclusions: These data demonstrate that combined MEK/mTOR inhibition is synergistic in glioblastoma cell lines and may be more potent in NF1-deficient glioblastoma.
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http://dx.doi.org/10.1093/noajnl/vdaa138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668446PMC
October 2020

Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor.

Clin Cancer Res 2021 02 23;27(4):1184-1194. Epub 2020 Nov 23.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Desmoplastic small round cell tumor (DSRCT) is a highly lethal intra-abdominal sarcoma of adolescents and young adults. DSRCT harbors a t(11;22)(p13:q12) that generates the EWSR1-WT1 chimeric transcription factor, the key oncogenic driver of DSRCT. EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that together mediate oncogenesis. EWSR1-WT1 also activates a neural gene expression program.

Experimental Design: Among these neural markers, we found prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3), a druggable receptor tyrosine kinase. We investigated the regulation of NTRK3 by EWSR1-WT1 and its potential as a therapeutic target and , the latter using novel patient-derived models of DSRCT.

Results: We found that EWSR1-WT1 binds upstream of and activates its transcription. NTRK3 mRNA is highly expressed in DSRCT compared with other major chimeric transcription factor-driven sarcomas and most DSRCTs are strongly immunoreactive for NTRK3 protein. Remarkably, expression of kinase domain mRNA in DSRCT is also higher than in cancers with fusions. Abrogation of NTRK3 expression by RNAi silencing reduces growth of DSRCT cells and pharmacologic targeting of NTRK3 with entrectinib is effective in both and models of DSRCT.

Conclusions: Our results indicate that EWSR1-WT1 directly activates NTRK3 expression in DSRCT cells, which are dependent on its expression and activity for growth. Pharmacologic inhibition of NTRK3 by entrectinib significantly reduces growth of DSRCT cells both and , providing a rationale for clinical evaluation of NTRK3 as a therapeutic target in DSRCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212565PMC
February 2021

Activation of Receptor Tyrosine Kinases Mediates Acquired Resistance to MEK Inhibition in Malignant Peripheral Nerve Sheath Tumors.

Cancer Res 2021 02 17;81(3):747-762. Epub 2020 Nov 17.

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Malignant peripheral nerve sheath tumors often arise in patients with neurofibromatosis type 1 and are among the most treatment-refractory types of sarcoma. Overall survival in patients with relapsed disease remains poor, and thus novel therapeutic approaches are needed. NF1 is essential for negative regulation of RAS activity and is altered in about 90% of malignant peripheral nerve sheath tumors (MPNST). A complex interplay of upstream signaling and parallel RAS-driven pathways characterizes NF1-driven tumorigenesis, and inhibiting more than one RAS effector pathway is therefore necessary. To devise potential combination therapeutic strategies, we identified actionable alterations in signaling that underlie adaptive and acquired resistance to MEK inhibitor (MEKi). Using a series of proteomic, biochemical, and genetic approaches in an model of MEKi resistance provided a rationale for combination therapies. HGF/MET signaling was elevated in the MEKi-resistant model. HGF overexpression conferred resistance to MEKi in parental cells. Depletion of HGF or MET restored sensitivity of MEKi-resistant cells to MEKi. Finally, a combination of MEK and MET inhibition demonstrated activity in models of MPNST and may therefore be effective in patients with MPNST harboring genetic alterations in . SIGNIFICANCE: This study demonstrates that MEKi plus MET inhibitor may delay or prevent a novel mechanism of acquired MEKi resistance, with clinical implications for MPNST patients harboring alterations.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854512PMC
February 2021

Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors.

Cancer Res 2020 12 8;80(23):5367-5379. Epub 2020 Oct 8.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, we have identified global activation of upstream receptor tyrosine kinases (RTK) that converges on activation of RAS as a mechanism to limit sensitivity to MEK inhibition. As no direct inhibitors of pan-RAS were available, an inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, represented an alternate strategy. The combination of MEKi plus SHP099 was superior to MEKi alone in models of NF1-MPNST, including those with acquired resistance to MEKi. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST harboring alterations in . SIGNIFICANCE: Combined inhibition of MEK and SHP2 is effective in models of NF1-MPNST, both those naïve to and those resistant to MEKi, as well as in the MPNST precursor lesion plexiform neurofibroma.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739379PMC
December 2020

-associated metastatic abdominopelvic primitive neuroectodermal tumor with an rearrangement in a 16-yr-old female.

Cold Spring Harb Mol Case Stud 2020 10 7;6(5). Epub 2020 Oct 7.

Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.

We report a case of a -associated -rearranged malignant primitive neuroectodermal tumor (PNET) arising in a patient with DICER1 tumor predisposition syndrome. A 16-yr-old female with a history of multinodular goiter presented with a widely metastatic abdominal small round blue cell tumor with neuroectodermal differentiation. gene rearrangement was identified in the tumor by fluorescence in situ hybridization (FISH). Genetic analysis revealed biallelic pathogenic variation. The patient was treated with an aggressive course of chemotherapy, surgery, and radiation with complete pathologic response. We believe this case to represent a new expression of the DICER1 tumor predisposition syndrome, an entity caused by deleterious germline mutations in the gene, encoding a ribonuclease active in the processing of miRNA. Patients with germline mutations in develop a diverse group of benign and malignant tumors. Some of these tumors have been noted to have immature neuroepithelium as a component, including the ciliary body medulloepithelioma and the recently described -associated presacral malignant teratoid neoplasm. To our knowledge, abdominal sarcomas that resemble PNET histology with an rearrangement have not previously been described as a classical expression of the DICER1 syndrome phenotype.
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http://dx.doi.org/10.1101/mcs.a005603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552927PMC
October 2020

Socioeconomic and health care coverage disparities in children, adolescents, and young adults with sarcoma.

Pediatr Blood Cancer 2020 12 17;67(12):e28708. Epub 2020 Sep 17.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Socioeconomic and health care coverage disparities are established as poor prognostic markers in adults with sarcoma, but few studies examine these differences among pediatric, adolescents and young adults (AYA). This study examines the association between socioeconomic status (SES), insurance status, and disease presentation among children and AYA patients with sarcoma.

Methods: This is a retrospective cohort study of patients aged 0-25 years with bone or soft tissue sarcoma from the National Cancer Database. SES assignments were based on estimated median income and education level. Patient demographics and clinical factors were compared by SES and insurance status. Multivariate logistic regression models were fitted to determine adjusted odds ratios of SES and insurance status on metastatic disease or tumor size ≥5 cm at time of presentation.

Results: In a cohort of 9112 patients, 2932 (32.1%) had low, 2084 (22.8%) middle, and 4096 (44.9%) high SES. For insurance status, 5864 (64.3%) had private, 2737 (30.0%) public, and 511 (5.6%) were uninsured. Compared to high SES, patients with low SES were more likely to have metastatic disease (OR = 1.16, P = .03) and tumors ≥5 cm (OR = 1.29, P < .01). Compared to private insurance, public and no insurance were associated with metastatic disease (OR = 1.35, P < .01 and OR = 1.32, P = .02) and increased tumors ≥5 cm (OR = 1.28, P < .01 and OR = 1.67, P < .01).

Conclusions: SES disparities exist among children and AYA patients with sarcoma. Low SES and public or no insurance are associated with advanced disease at presentation. Further studies are needed to identify interventions to improve earlier detection of sarcomas in at-risk children and young adults.
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http://dx.doi.org/10.1002/pbc.28708DOI Listing
December 2020

Special Issue: "Genomics and Models of Nerve Sheath Tumors".

Genes (Basel) 2020 09 1;11(9). Epub 2020 Sep 1.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Nerve sheath tumors arising in the context of neurofibromatosis type 1 (NF1) include benign tumors such as cutaneous, diffuse and plexiform neurofibromas; atypical neurofibromas or atypical neurofibromatosis neoplasms of uncertain biological potential (ANNUBP); and the aggressive soft tissue sarcoma, the malignant peripheral nerve sheath tumor (MPNST) [...].
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http://dx.doi.org/10.3390/genes11091024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563428PMC
September 2020

From Genes to -Omics: The Evolving Molecular Landscape of Malignant Peripheral Nerve Sheath Tumor.

Genes (Basel) 2020 06 24;11(6). Epub 2020 Jun 24.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, 401 N Broadway, Baltimore, MD 21231, USA.

Malignant peripheral nerve sheath tumors (MPNST) are rare, aggressive soft tissue sarcomas that occur with significantly increased incidence in people with the neuro-genetic syndrome neurofibromatosis type I (NF1). These complex karyotype sarcomas are often difficult to resect completely due to the involvement of neurovascular bundles, and are relatively chemotherapy- and radiation-insensitive. The lifetime risk of developing MPNST in the NF1 population has led to great efforts to characterize the genetic changes that drive the development of these tumors and identify mutations that may be used for diagnostic or therapeutic purposes. Advancements in genetic sequencing and genomic technologies have greatly enhanced researchers' abilities to broadly and deeply investigate aberrations in human MPNST genomes. Here, we review genetic sequencing efforts in human MPNST samples over the past three decades. Particularly for NF1-associated MPNST, these overall sequencing efforts have converged on a set of four common genetic changes that occur in most MPNST, including mutations in neurofibromin 1 (), , , and members of the polycomb repressor complex 2 (PRC2). However, broader genomic studies have also identified recurrent but less prevalent genetic variants in human MPNST that also contribute to the molecular landscape of MPNST and may inform further research. Future studies to further define the molecular landscape of human MPNST should focus on collaborative efforts across multiple institutions in order to maximize information gathered from large numbers of well-annotated MPNST patient samples, both in the NF1 and the sporadic MPNST populations.
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http://dx.doi.org/10.3390/genes11060691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349243PMC
June 2020

A clinically and genomically annotated nerve sheath tumor biospecimen repository.

Sci Data 2020 06 19;7(1):184. Epub 2020 Jun 19.

Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA.

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.
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http://dx.doi.org/10.1038/s41597-020-0508-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305302PMC
June 2020

FLT3-IRAK dual targeting: an exciting new therapeutic option guided by adaptive activation of immune response pathways.

Ann Transl Med 2020 Apr;8(7):511

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.

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http://dx.doi.org/10.21037/atm.2020.01.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210206PMC
April 2020

BRAF V600E-mutated metastatic pediatric Wilms tumor with complete response to targeted RAF/MEK inhibition.

Cold Spring Harb Mol Case Stud 2020 04 1;6(2). Epub 2020 Apr 1.

Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21287, USA.

Wilms tumor (WT) is the most common renal malignancy of childhood and accounts for 6% of all childhood malignancies. With current therapies, the 5-yr overall survival (OS) for children with unilateral favorable histology WT is greater than 85%. The prognosis is worse, however, for the roughly 15% of patients who relapse, with only 50%-80% OS reported in those with recurrence. Herein, we describe the extended and detailed clinical course of a rare case of a child with recurrent, pulmonary metastatic, favorable histology WT harboring a BRAF V600E mutation. The BRAF V600E mutation, commonly found in melanoma and other cancers, and previously undescribed in WT, has recently been reported by our group in a subset of epithelial-predominant WT. This patient, who was included in that series, presented with unilateral, stage 1, favorable histology WT and was treated with standard chemotherapy. Following the completion of therapy, the patient relapsed with pulmonary metastatic disease, that then again recurred despite an initial response to salvage chemotherapy and radiation. Next-generation sequencing (NGS) on the metastatic pulmonary nodule revealed a BRAF V600E mutation. After weighing the therapeutic options, a novel approach with dual BRAF/MEK inhibitor combination therapy was initiated. Complete radiographic response was observed following 4 months of therapy with dabrafenib and trametinib. At 12 months following the start of BRAF/MEK combination treatment, the patient continues with a complete response and has experienced minimal treatment-related side effects. This represents the first case, to our knowledge, of effective treatment with BRAF/MEK molecularly targeted therapy in a pediatric Wilms tumor patient.
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http://dx.doi.org/10.1101/mcs.a004820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133746PMC
April 2020

Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1.

Genes (Basel) 2020 02 21;11(2). Epub 2020 Feb 21.

Computational Oncology, Sage Bionetworks, Seattle, WA 98121, USA.

Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40-60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.
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http://dx.doi.org/10.3390/genes11020226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073563PMC
February 2020

A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory V600 Mutation-Positive Solid Tumors.

Clin Cancer Res 2019 12 10;25(24):7294-7302. Epub 2019 Sep 10.

The Hospital for Sick Children, University of Toronto, Department of Pediatrics, Toronto, Ontario.

Purpose: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced V600-mutated cancers.

Patients And Methods: This phase I dose-finding part treated patients ages 1 to <18 years with V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target.

Results: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily.

Conclusions: In this first clinical trial in pediatric patients with pretreated V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3572DOI Listing
December 2019

BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors.

Cancers (Basel) 2019 Aug 28;11(9). Epub 2019 Aug 28.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA.

BRAF mutations have been identified as targetable, oncogenic mutations in many cancers. Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest. In this review, we present the spectrum of BRAF mutations and fusion alterations present in each class of primary brain tumor based on publicly available databases and publications. We also summarize clinical experience with RAF and MEK inhibitors in patients with primary brain tumors and describe ongoing clinical trials of RAF inhibitors in glioma. Sensitivity to RAF and MEK inhibitors varies among BRAF mutations and between tumor types as only class I BRAF V600 mutations are sensitive to clinically available RAF inhibitors. While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors. We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population.
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http://dx.doi.org/10.3390/cancers11091262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769482PMC
August 2019

Telomere alterations in neurofibromatosis type 1-associated solid tumors.

Acta Neuropathol Commun 2019 08 28;7(1):139. Epub 2019 Aug 28.

Departments of Pathology, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD, 21231, USA.

The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.
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http://dx.doi.org/10.1186/s40478-019-0792-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712691PMC
August 2019

A novel RBMX-TFE3 gene fusion in a highly aggressive pediatric renal perivascular epithelioid cell tumor.

Genes Chromosomes Cancer 2019 Aug 13. Epub 2019 Aug 13.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX-TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12-year-old boy who presented with a large left renal mass with extension into the inferior vena cava. The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break-apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX-TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come-together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break-apart might be below the FISH resolution, resulting in a false negative result.
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http://dx.doi.org/10.1002/gcc.22801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057291PMC
August 2019

Metanephric Adenoma-Epithelial Wilms Tumor Overlap Lesions: An Analysis of BRAF Status.

Am J Surg Pathol 2019 09;43(9):1157-1169

Departments of Pathology.

Metanephric adenoma (MA) has historically been considered to represent a differentiated form of epithelial Wilms tumor (WT), based in part upon cases that morphologically overlap these 2 neoplasms. More recently, BRAF V600E mutations have been demonstrated in the majority of MAs but not in unselected or even epithelial-predominant WTs, suggesting 2 genetically distinct entities. However, no prior study has examined BRAF status in neoplasms with overlapping histologic features of epithelial WT and MA. We studied a cohort of 11 such overlapping lesions, 2 of which we considered morphologically to be otherwise typical MAs with unusually prominent mitotic activity and 9 of which we classified as epithelial WTs with areas resembling MA. Both mitotically active MAs demonstrated the BRAF V600E mutation. While the majority (5/9) of epithelial WTs with areas resembling MA were negative for BRAF V600E mutation, 4 such cases were positive. Two BRAF V600E mutation-positive WTs occurred in children. One case in a 6-year-old male was morphologically similar to the BRAF V600E mutation-positive adult cases and subsequently metastasized to the lungs; remarkably, the metastases then completely resolved on Braf targeted therapy. A second occurred in a 3-year-old girl whose posttherapy nephrectomy specimen's tumor was encapsulated and mitotically active like a typical WT, but also had more differentiated areas resembling MA. Immunohistochemistry for Braf V600E paralleled the molecular findings, demonstrating immunoreactivity in both the WT and MA-like areas of all 4 of these neoplasms. In summary, we demonstrate that BRAF V600E mutations are not entirely restricted to typical MA, as they may be seen in MAs showing mitotic activity along with a subset of epithelial-predominant WTs in adults and children that have foci which overlap morphologically with MA.
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http://dx.doi.org/10.1097/PAS.0000000000001240DOI Listing
September 2019

Rare BRAF mutations in pancreatic neuroendocrine tumors may predict response to RAF and MEK inhibition.

PLoS One 2019 3;14(6):e0217399. Epub 2019 Jun 3.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

The clinical significance of BRAF alterations in well-differentiated (WD) metastatic pancreatic neuroendocrine tumor (panNET) is unknown, but BRAF-mutated panNET could represent a subset characterized by an identifiable and clinically actionable driver. Following the identification of two patients with WD metastatic panNET whose tumors harbored BRAF mutations, we queried the MSK-IMPACT series of 80 patients with WD metastatic panNET for additional mutations in BRAF, and in other genes involved in RAS/ RTK/ PI3K signaling pathways. BRAF mutations were identified in six samples (7.5%): two tumors harbored V600E mutations, one tumor each expressed K601E, T599K, and T310I mutations, and one tumor expressed both G596D and E451K BRAF. Few additional actionable driver alterations were identified. To determine the ERK activating capability of four BRAF mutations not previously characterized, mutant constructs were tested in model systems. Biochemical characterization of BRAF mutations revealed both high and low activity mutants. Engineered cells expressing BRAF K601E and V600E were used for in vitro drug testing of RAF and MEK inhibitors currently in clinical use. BRAF K601E demonstrated reduced sensitivity to dabrafenib compared to BRAF V600E, but the combination of RAF plus MEK inhibition was effective in cells expressing this mutation. Herein, we describe the clinical course of a patient with BRAF K601E and a patient with BRAF V600E WD metastatic panNET, and the identification of four mutations in BRAF not previously characterized. The combined clinical and biochemical data support a potential role for RAF and MEK inhibitors, or a combination of these, in a selected panNET population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546234PMC
February 2020

Author Correction: The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling.

Nat Cell Biol 2019 04;21(4):534

Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065, USA.

In the version of this Article originally published the same blot was inadvertently presented as both p-Rb and Cyclin A in Fig. 2a. This blot corresponds to the p-Rb panel, as can be seen in the unprocessed version of these blots in Supplementary Fig. 9. The corrected version of the panel is shown below, together with a completely uncropped image of both blots. In addition, in the 'Viral transduction' section of the Methods, the pLKO.1 plasmids encoding short hairpin RNAs targeting human Rnd1 were incorrectly listed as clones TRCN0000018338 and TRCN0000039977. The correct clone numbers are TRCN0000047434 and TRCN0000047435.
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http://dx.doi.org/10.1038/s41556-019-0288-3DOI Listing
April 2019

Sporadic Malignant Glomus Tumor of the Brachial Plexus With Response to Targeted Therapy Directed Against Oncogenic .

JCO Precis Oncol 2018 4;2018. Epub 2018 May 4.

Johns Hopkins University School of Medicine. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292440PMC
http://dx.doi.org/10.1200/PO.17.00261DOI Listing
May 2018

Eosinophilic Solid and Cystic (ESC) Renal Cell Carcinomas Harbor TSC Mutations: Molecular Analysis Supports an Expanding Clinicopathologic Spectrum.

Am J Surg Pathol 2018 09;42(9):1166-1181

Johns Hopkins University School of Medicine, Pathology and Oncology, Baltimore, MD.

Eosinophilic solid and cystic (ESC) renal cell carcinoma (RCC) has recently been described as a potentially new subtype of RCC based upon morphologic and immunohistochemical features. These neoplasms typically demonstrate solid and cystic architecture, and the neoplastic cells contain voluminous eosinophilic cytoplasm with granular cytoplasmic stippling. There is frequently focal immunoreactivity for cytokeratin 20. Although the initial cases all occurred in adult females and had benign outcome, we recently expanded the proposed spectrum of this neoplasm to include pediatric cases, multifocal neoplasms, and a case with hematogenous metastasis. ESC has been postulated to be analogous to a subtype of RCC consistently identified in tuberous sclerosis complex patients, and while previous work has demonstrated loss of heterozygosity at the TSC1 locus and copy number gains at TSC2 in ESC RCC, these genes have not been sequenced in ESC RCC. Using capture-based and amplicon-based next-generation sequencing, we now demonstrate the consistent presence of either TSC1 or TSC2 gene mutations in pediatric ESC RCC (8/9 cases) and adult ESC RCC (6/6 cases). These included a metastatic ESC RCC which had a complete response to mTOR targeted therapy. We also found these mutations in some neoplasms with variant morphology and thus potentially expand the spectrum of ESC RCC. These include one of our adult cases which demonstrated dominant "type 2" papillary RCC morphology and 2 of 3 previously unclassified pediatric RCC with features of ESC RCC minus granular cytoplasmic stippling. We also demonstrate TSC mutations in a case of so-called "oncocytoid RCC after neuroblastoma" with identical morphology and immunoprofile, providing a molecular link between the latter and ESC RCC. In summary, ESC RCC consistently harbors actionable TSC1 or TSC2 mutations, which are infrequently seen in established subtypes of RCC. These findings support TSC1/2 mutation as a molecular marker of ESC RCC, and suggest expansion of the clinicopathologic spectrum to include neoplasms with papillary architecture, occasional cases lacking well-developed granular cytoplasmic stippling, and a subset of RCC with oncocytic features in patients who have survived neuroblastoma.
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http://dx.doi.org/10.1097/PAS.0000000000001111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089659PMC
September 2018
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