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Papers by Christopher Moertel

Research paper thumbnail of Maternal Contraceptive Use and Central Nervous System Tumors in Offspring

Research paper thumbnail of Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis Type I and Scoliosis

Research paper thumbnail of Abstract 1614: Creation of malignant peripheral nerve sheath tumor models deficient for polycomb repressive complex 2 and identification of therapeutic vulnerabilities

Cancer Research, Jun 15, 2022

We constructed models of nerve sheath tumors that arise in Neurofibromatosis Type 1 (NF1) patient... more We constructed models of nerve sheath tumors that arise in Neurofibromatosis Type 1 (NF1) patients and conducted therapeutics discovery using synthetic lethal pharmacogenomic screens. Given both plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs) arise within the Schwann cell lineage, we developed a drug discovery pipeline to identify targeted therapeutics for treating NF1-related neoplasia. Using CRISPR/Cas9, immortalized human Schwann cell lines were created lacking the NF1 gene or NF1 and components of Polycomb Repressive Complex 2 (PRC2), such as SUZ12. ~80% of all MPNST harbor loss of function mutations in PRC2 genes, which is highly suggestive that perturbation of epigenetic homeostasis plays a role in malignant transformation of neurofibromas. Our models mimic the genetics of MPNSTs and allowed us to identify selectively lethal drugs which exploit vulnerabilities specific to these genetic drivers. We describe the identification of these novel drugs, extensive in vivo testing in models of MPNST, and mechanistic studies to explain why they act specifically on MPNSTs. We identified compounds showing selective lethality towards NF1/SUZ12 double mutant cells. These include drugs affecting epigenetic homeostasis, such as HDAC inhibitors (HDACi). Moreover, many of these drugs showed strong synergy when tested in combination with a MEK inhibitor (MEKi) against NF1/SUZ12 deficient human Schwann and MPNST cell lines. We investigated the mechanism of this synergy using genetics, transcriptome, and proteome analysis. Interestingly, these mechanistic studies revealed possible emerging avenues of resistance the cells are utilizing to compensate for and survive therapeutic intervention. For instance, proteomics analysis of PRC2 deficient MPNST cell lines treated with combination therapy of MEKi and HDACi indicates activation of specific survival and stress response pathways. Targeting these pathways in conjunction with the therapeutics we have identified could prevent emergence of resistance and tumor escape. Clinically interesting drug candidates were advanced and tested as single agents and in combination in multiple in vivo models of MPNST (including patient derived and cell line xenografts). The FDA approved drugs vorinostat (HDACi) and selumetinib (MEKi) have shown dramatic efficacy, with combination therapy exhibiting strong synergy in vivo. This includes durable responses in survival studies and the ability to dramatically shrink established tumors, with treated tumors showing markers of apoptosis. The discovery of novel agents effective against several models of MPNST is exciting as there are currently no approved targeted therapies for MPNSTs. Our results implicate targeting of epigenetic homeostasis, in combination with MEKi, as a major vulnerability of MPNSTs deficient for PRC2 activity. Citation Format: Kyle B. Williams, Alex Larsson, Justin Tibbits, Christopher L. Moertel, David A. Largaespada. Creation of malignant peripheral nerve sheath tumor models deficient for polycomb repressive complex 2 and identification of therapeutic vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1614.

Research paper thumbnail of #642 Increased incidence of acquired anemia among Laotian-Hmong children in Minnesota: results of the St. Paul/Ramsey County childhood anemia project

The American journal of pediatric hematology/oncology, Jul 1, 1997

Research paper thumbnail of Acute Idiopathic Thrombocytopenic Purpura — Management in Childhood

Research paper thumbnail of RARE-11. Perinatal Diffuse Infiltrating Brainstem Glioma: Case Report and Review of the Literature

Neuro-oncology, Nov 1, 2016

Research paper thumbnail of Supplementary Figure 2 from <i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

PDF file - 137K, Effect of Nf1 dosage with Pten inactivation in peripheral nerve tumorigenesis

Research paper thumbnail of Supplementary Figure 4 from <i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

PDF file - 93K, Semi-quantitative analysis of proliferative peripheral nerve cells in various con... more PDF file - 93K, Semi-quantitative analysis of proliferative peripheral nerve cells in various control and experimental cohorts

Research paper thumbnail of Supplementary Figure 3 from <i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

PDF file - 181K, Histological and immunohistochemical (IHC) analyses of peripheral nervous system... more PDF file - 181K, Histological and immunohistochemical (IHC) analyses of peripheral nervous system phenotype

Research paper thumbnail of Supplementary Figure 1 from <i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

PDF file - 80K, Transgenes used to establish a novel PNST mouse model

Research paper thumbnail of #671 Catheter-directed continuous infusion urokinase thrombolysis (CIUK) in children under 19 years

Journal of Pediatric Hematology Oncology, Jul 1, 1998

Research paper thumbnail of The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas

International journal of molecular sciences, Apr 17, 2024

Research paper thumbnail of An Unusual Pelvic Mass in a Pediatric Patient: A Case Report and Review of the Pathology

Journal of Pediatric Hematology Oncology, May 1, 2017

Neurofibromatosis type 1 (NF1) is the most commonly inherited autosomal dominant disorder in huma... more Neurofibromatosis type 1 (NF1) is the most commonly inherited autosomal dominant disorder in humans. NF1 patients have increased risk for gastrointestinal stromal tumors (GISTs). A Meckel&amp;amp;#39;s diverticulum (MD) represents a persistent embryonic omphalomesenteric duct characterized as a true diverticulum located near the ileocecal valve. We report a unique clinical case whereby a patient with NF1 developed a GIST within a MD. An adolescent male with NF1 presented with persistent lower abdominal pain. Clinical evaluation demonstrated a large pelvic mass. In the operating room, the mass was noted to emerge from a MD. Final pathology demonstrated a GIST with negative margins and CD117 positivity. Patients with NF1 are at increased risk for mesenchymal tumors including malignant peripheral nerve sheath tumors. GISTs are the most important and frequent non-neurological malignancy in NF1 and develop in ∼7% of NF1 patients. GISTs tend to be multifocal in NF1; however, they rarely occur within a Meckel&amp;amp;#39;s diverticula. Our case represents a rare case of a patient with NF1 who developed a symptomatic GIST within a MD. We recommend utilizing laparoscopy to determine resectability and clarify the diagnosis in this unique patient population who are at risk for multiple neoplasms.

Research paper thumbnail of Correction: Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity

Oncotarget, Sep 29, 2020

Figure 2: Phosphorylated ERK is diminished in response to increasing dosing of PD0325901 in the t... more Figure 2: Phosphorylated ERK is diminished in response to increasing dosing of PD0325901 in the trigeminal nerves of Dhh-Cre; Pten fl/fl ; Nf1 fl/fl mice. In this western blot, activated ERK is diminished when PD901 was administered IP acutely 2 hours before sacrifice (Cell Signaling 4377S). At 5mg/kg, signal was ablated completely. In a contrasting manner, p-AKT (Cell Signaling 4075S) levels seemingly increased in the trigeminal nerves in a dose-dependent fashion. This correlates with a potential signaling feedback and resistance mechanism of monotherapeutic targeted treatment. Quantifications for phospho-AKT/total-AKT and phospho-ERK/total-ERK are pictured on the right panel.

Research paper thumbnail of Iron-deficiency anemia in bottle-fed toddlers

Research paper thumbnail of Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)–associated plexiform neurofibroma: A phase I/IIa study

Journal of Clinical Oncology, May 20, 2018

10504Background: NF-1 loss-of-function alterations are associated with development of plexiform n... more 10504Background: NF-1 loss-of-function alterations are associated with development of plexiform neurofibromas (PNs). NF-1–associated PNs can arise early in life in different locations, with variabl...

Research paper thumbnail of Expression of Somatostatin Receptors in Childhood Neuroblastoma

American Journal of Clinical Pathology, Dec 1, 1994

Somatostatin receptors are expressed on certain neural crest-derived tumors, including pancreatic... more Somatostatin receptors are expressed on certain neural crest-derived tumors, including pancreatic islet cell and carcinoid tumors, medullary thyroid carcinomas, pheochromocytomas, and paragangliomas. The authors evaluated the expression of high affinity somatostatin receptors in childhood neuroblastoma using autoradiography techniques with the somatostatin analogue 125I-octreotide or 125I-[Leu8,D-Trp22,Tyr25]-SS-28 as the radioligand. Thirty tumors from 30 children with neuroblastoma were analyzed. Twenty-three of 30 tumors that were tested expressed somatostatin receptors. Correlation of somatostatin receptor expression with survival was statistically significant. The survival of those patients whose tumors expressed somatostatin receptors was of longer duration than that of patients whose tumors did not. This was an independent prognostic factor. Somatostatin receptors were expressed more frequently in tumor tissue from patients with lower stages of disease and in those with no evidence of N-myc amplification. Tumoral somatostatin receptors are expressed in a subgroup of patients with childhood neuroblastoma. Survival analysis in this group of patients indicates that somatostatin receptor expression is a favorable prognostic factor. This finding may have important implications for the therapy of children with this malignancy.

Research paper thumbnail of Whole Blood Tissue Factor Procoagulant Activity Is Elevated in Patients With Sickle Cell Disease

Research paper thumbnail of Sex differences in methylation profiles are apparent in medulloblastoma, particularly among SHH tumors

Frontiers in Oncology, Mar 24, 2023

Background: Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex... more Background: Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex differences in prevalence of the four main molecular subgroups: SHH, WNT, Group 3 and Group 4. Males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Little is known about sex differences in methylation profiles within subgroups. M e t h o d s : U s i n g p u b l i c l y a v a i l a b l e m e t h y l a t i o n d a t a (I l l u m i n a HumanMethylation450K array), we compared beta values for males versus females. Differentially methylated positions (DMP) by sex within medulloblastoma subgroups were identified on the autosomes. DMPs were mapped to genes and Reactome pathway analysis was run by subgroup. Kaplan-Meier survival curves (Log-Rank p-values) were assessed for each sex within subgroup. MethylCIBERSORT was used to investigate the tumor microenvironment using deconvolution to estimate the abundances of immune cell types using DNA methylation data. Results: There were statistically significant differences in sex by medulloblastoma subgroups (chi-squared p-value=0.00004): Group 3 (n=144; 65% male), Group 4 (n=326; 67% male), SHH (n=223; 57% male) and WNT (n=70; 41% male). Females had worse survival than males for SHH (p-value=0.02). DMPs by sex were identified within subgroups: SHH (n=131), Group 4 (n=29), Group 3 (n=19), and WNT (n=16) and validated in an independent dataset. Unsupervised hierarchical clustering showed that sex-DMPs in SHH did not correlate with other tumor attributes. Ten genes with sex DMPs (RFTN1, C1orf103, FKBP1B, Frontiers in Oncology frontiersin.org 01

Research paper thumbnail of Phase 1 trial of trametinib alone and in combination with dabrafenib in children and adolescents with relapsed solid tumors or neurofibromatosis type 1 (NF1) progressive plexiform neurofibromas (PN)

Journal of Clinical Oncology, May 20, 2018

10537Background: Mitogen-activated protein kinase (MAPK) pathway aberrations are common in cancer... more 10537Background: Mitogen-activated protein kinase (MAPK) pathway aberrations are common in cancer and NF1 PN. Dabrafenib, a BRAF inhibitor, is active in children with BRAF V600–mutant tumors; howev...

Research paper thumbnail of Maternal Contraceptive Use and Central Nervous System Tumors in Offspring

Research paper thumbnail of Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis Type I and Scoliosis

Research paper thumbnail of Abstract 1614: Creation of malignant peripheral nerve sheath tumor models deficient for polycomb repressive complex 2 and identification of therapeutic vulnerabilities

Cancer Research, Jun 15, 2022

We constructed models of nerve sheath tumors that arise in Neurofibromatosis Type 1 (NF1) patient... more We constructed models of nerve sheath tumors that arise in Neurofibromatosis Type 1 (NF1) patients and conducted therapeutics discovery using synthetic lethal pharmacogenomic screens. Given both plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs) arise within the Schwann cell lineage, we developed a drug discovery pipeline to identify targeted therapeutics for treating NF1-related neoplasia. Using CRISPR/Cas9, immortalized human Schwann cell lines were created lacking the NF1 gene or NF1 and components of Polycomb Repressive Complex 2 (PRC2), such as SUZ12. ~80% of all MPNST harbor loss of function mutations in PRC2 genes, which is highly suggestive that perturbation of epigenetic homeostasis plays a role in malignant transformation of neurofibromas. Our models mimic the genetics of MPNSTs and allowed us to identify selectively lethal drugs which exploit vulnerabilities specific to these genetic drivers. We describe the identification of these novel drugs, extensive in vivo testing in models of MPNST, and mechanistic studies to explain why they act specifically on MPNSTs. We identified compounds showing selective lethality towards NF1/SUZ12 double mutant cells. These include drugs affecting epigenetic homeostasis, such as HDAC inhibitors (HDACi). Moreover, many of these drugs showed strong synergy when tested in combination with a MEK inhibitor (MEKi) against NF1/SUZ12 deficient human Schwann and MPNST cell lines. We investigated the mechanism of this synergy using genetics, transcriptome, and proteome analysis. Interestingly, these mechanistic studies revealed possible emerging avenues of resistance the cells are utilizing to compensate for and survive therapeutic intervention. For instance, proteomics analysis of PRC2 deficient MPNST cell lines treated with combination therapy of MEKi and HDACi indicates activation of specific survival and stress response pathways. Targeting these pathways in conjunction with the therapeutics we have identified could prevent emergence of resistance and tumor escape. Clinically interesting drug candidates were advanced and tested as single agents and in combination in multiple in vivo models of MPNST (including patient derived and cell line xenografts). The FDA approved drugs vorinostat (HDACi) and selumetinib (MEKi) have shown dramatic efficacy, with combination therapy exhibiting strong synergy in vivo. This includes durable responses in survival studies and the ability to dramatically shrink established tumors, with treated tumors showing markers of apoptosis. The discovery of novel agents effective against several models of MPNST is exciting as there are currently no approved targeted therapies for MPNSTs. Our results implicate targeting of epigenetic homeostasis, in combination with MEKi, as a major vulnerability of MPNSTs deficient for PRC2 activity. Citation Format: Kyle B. Williams, Alex Larsson, Justin Tibbits, Christopher L. Moertel, David A. Largaespada. Creation of malignant peripheral nerve sheath tumor models deficient for polycomb repressive complex 2 and identification of therapeutic vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1614.

Research paper thumbnail of #642 Increased incidence of acquired anemia among Laotian-Hmong children in Minnesota: results of the St. Paul/Ramsey County childhood anemia project

The American journal of pediatric hematology/oncology, Jul 1, 1997

Research paper thumbnail of Acute Idiopathic Thrombocytopenic Purpura — Management in Childhood

Research paper thumbnail of RARE-11. Perinatal Diffuse Infiltrating Brainstem Glioma: Case Report and Review of the Literature

Neuro-oncology, Nov 1, 2016

Research paper thumbnail of Supplementary Figure 2 from <i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

PDF file - 137K, Effect of Nf1 dosage with Pten inactivation in peripheral nerve tumorigenesis

Research paper thumbnail of Supplementary Figure 4 from <i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

PDF file - 93K, Semi-quantitative analysis of proliferative peripheral nerve cells in various con... more PDF file - 93K, Semi-quantitative analysis of proliferative peripheral nerve cells in various control and experimental cohorts

Research paper thumbnail of Supplementary Figure 3 from <i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

PDF file - 181K, Histological and immunohistochemical (IHC) analyses of peripheral nervous system... more PDF file - 181K, Histological and immunohistochemical (IHC) analyses of peripheral nervous system phenotype

Research paper thumbnail of Supplementary Figure 1 from <i>PTEN</i> and <i>NF1</i> Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors

PDF file - 80K, Transgenes used to establish a novel PNST mouse model

Research paper thumbnail of #671 Catheter-directed continuous infusion urokinase thrombolysis (CIUK) in children under 19 years

Journal of Pediatric Hematology Oncology, Jul 1, 1998

Research paper thumbnail of The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas

International journal of molecular sciences, Apr 17, 2024

Research paper thumbnail of An Unusual Pelvic Mass in a Pediatric Patient: A Case Report and Review of the Pathology

Journal of Pediatric Hematology Oncology, May 1, 2017

Neurofibromatosis type 1 (NF1) is the most commonly inherited autosomal dominant disorder in huma... more Neurofibromatosis type 1 (NF1) is the most commonly inherited autosomal dominant disorder in humans. NF1 patients have increased risk for gastrointestinal stromal tumors (GISTs). A Meckel&amp;amp;#39;s diverticulum (MD) represents a persistent embryonic omphalomesenteric duct characterized as a true diverticulum located near the ileocecal valve. We report a unique clinical case whereby a patient with NF1 developed a GIST within a MD. An adolescent male with NF1 presented with persistent lower abdominal pain. Clinical evaluation demonstrated a large pelvic mass. In the operating room, the mass was noted to emerge from a MD. Final pathology demonstrated a GIST with negative margins and CD117 positivity. Patients with NF1 are at increased risk for mesenchymal tumors including malignant peripheral nerve sheath tumors. GISTs are the most important and frequent non-neurological malignancy in NF1 and develop in ∼7% of NF1 patients. GISTs tend to be multifocal in NF1; however, they rarely occur within a Meckel&amp;amp;#39;s diverticula. Our case represents a rare case of a patient with NF1 who developed a symptomatic GIST within a MD. We recommend utilizing laparoscopy to determine resectability and clarify the diagnosis in this unique patient population who are at risk for multiple neoplasms.

Research paper thumbnail of Correction: Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity

Oncotarget, Sep 29, 2020

Figure 2: Phosphorylated ERK is diminished in response to increasing dosing of PD0325901 in the t... more Figure 2: Phosphorylated ERK is diminished in response to increasing dosing of PD0325901 in the trigeminal nerves of Dhh-Cre; Pten fl/fl ; Nf1 fl/fl mice. In this western blot, activated ERK is diminished when PD901 was administered IP acutely 2 hours before sacrifice (Cell Signaling 4377S). At 5mg/kg, signal was ablated completely. In a contrasting manner, p-AKT (Cell Signaling 4075S) levels seemingly increased in the trigeminal nerves in a dose-dependent fashion. This correlates with a potential signaling feedback and resistance mechanism of monotherapeutic targeted treatment. Quantifications for phospho-AKT/total-AKT and phospho-ERK/total-ERK are pictured on the right panel.

Research paper thumbnail of Iron-deficiency anemia in bottle-fed toddlers

Research paper thumbnail of Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)–associated plexiform neurofibroma: A phase I/IIa study

Journal of Clinical Oncology, May 20, 2018

10504Background: NF-1 loss-of-function alterations are associated with development of plexiform n... more 10504Background: NF-1 loss-of-function alterations are associated with development of plexiform neurofibromas (PNs). NF-1–associated PNs can arise early in life in different locations, with variabl...

Research paper thumbnail of Expression of Somatostatin Receptors in Childhood Neuroblastoma

American Journal of Clinical Pathology, Dec 1, 1994

Somatostatin receptors are expressed on certain neural crest-derived tumors, including pancreatic... more Somatostatin receptors are expressed on certain neural crest-derived tumors, including pancreatic islet cell and carcinoid tumors, medullary thyroid carcinomas, pheochromocytomas, and paragangliomas. The authors evaluated the expression of high affinity somatostatin receptors in childhood neuroblastoma using autoradiography techniques with the somatostatin analogue 125I-octreotide or 125I-[Leu8,D-Trp22,Tyr25]-SS-28 as the radioligand. Thirty tumors from 30 children with neuroblastoma were analyzed. Twenty-three of 30 tumors that were tested expressed somatostatin receptors. Correlation of somatostatin receptor expression with survival was statistically significant. The survival of those patients whose tumors expressed somatostatin receptors was of longer duration than that of patients whose tumors did not. This was an independent prognostic factor. Somatostatin receptors were expressed more frequently in tumor tissue from patients with lower stages of disease and in those with no evidence of N-myc amplification. Tumoral somatostatin receptors are expressed in a subgroup of patients with childhood neuroblastoma. Survival analysis in this group of patients indicates that somatostatin receptor expression is a favorable prognostic factor. This finding may have important implications for the therapy of children with this malignancy.

Research paper thumbnail of Whole Blood Tissue Factor Procoagulant Activity Is Elevated in Patients With Sickle Cell Disease

Research paper thumbnail of Sex differences in methylation profiles are apparent in medulloblastoma, particularly among SHH tumors

Frontiers in Oncology, Mar 24, 2023

Background: Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex... more Background: Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex differences in prevalence of the four main molecular subgroups: SHH, WNT, Group 3 and Group 4. Males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Little is known about sex differences in methylation profiles within subgroups. M e t h o d s : U s i n g p u b l i c l y a v a i l a b l e m e t h y l a t i o n d a t a (I l l u m i n a HumanMethylation450K array), we compared beta values for males versus females. Differentially methylated positions (DMP) by sex within medulloblastoma subgroups were identified on the autosomes. DMPs were mapped to genes and Reactome pathway analysis was run by subgroup. Kaplan-Meier survival curves (Log-Rank p-values) were assessed for each sex within subgroup. MethylCIBERSORT was used to investigate the tumor microenvironment using deconvolution to estimate the abundances of immune cell types using DNA methylation data. Results: There were statistically significant differences in sex by medulloblastoma subgroups (chi-squared p-value=0.00004): Group 3 (n=144; 65% male), Group 4 (n=326; 67% male), SHH (n=223; 57% male) and WNT (n=70; 41% male). Females had worse survival than males for SHH (p-value=0.02). DMPs by sex were identified within subgroups: SHH (n=131), Group 4 (n=29), Group 3 (n=19), and WNT (n=16) and validated in an independent dataset. Unsupervised hierarchical clustering showed that sex-DMPs in SHH did not correlate with other tumor attributes. Ten genes with sex DMPs (RFTN1, C1orf103, FKBP1B, Frontiers in Oncology frontiersin.org 01

Research paper thumbnail of Phase 1 trial of trametinib alone and in combination with dabrafenib in children and adolescents with relapsed solid tumors or neurofibromatosis type 1 (NF1) progressive plexiform neurofibromas (PN)

Journal of Clinical Oncology, May 20, 2018

10537Background: Mitogen-activated protein kinase (MAPK) pathway aberrations are common in cancer... more 10537Background: Mitogen-activated protein kinase (MAPK) pathway aberrations are common in cancer and NF1 PN. Dabrafenib, a BRAF inhibitor, is active in children with BRAF V600–mutant tumors; howev...