Publications by authors named "Derek A Oldridge"

24 Publications

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Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.

Sci Immunol 2021 03;6(57)

Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.
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http://dx.doi.org/10.1126/sciimmunol.abf7570DOI Listing
March 2021

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection.

Cell 2021 04 9;184(7):1858-1864.e10. Epub 2021 Feb 9.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the coronavirus disease 2019 (COVID-19) pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 431 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 251 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼20% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.cell.2021.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871851PMC
April 2021

Overview of methods for enhancing bone regeneration in distraction osteogenesis: Potential roles of biometals.

J Orthop Translat 2021 Mar 2;27:110-118. Epub 2021 Feb 2.

Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong.

Background: Distraction osteogenesis (DO) is a functional tissue engineering approach that applies gradual mechanical traction on the bone tissues after osteotomy to stimulate bone regeneration. However, DO still has disadvantages that limit its clinical use, including long treatment duration.

Methods: Review the current methods of promoting bone formation and consolidation in DO with particular interest on biometal.

Results: Numerous approaches, including physical therapy, gene therapy, growth factor-based therapy, stem-cell-based therapy, and improved distraction devices, have been explored to reduce the DO treatment duration with some success. Nevertheless, no approach to date is widely accepted in clinical practice due to various reasons, such as high expense, short biologic half-life, and lack of effective delivery methods. Biometals, including calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), manganese (Mn), and cobalt (Co) have attracted attention in bone regeneration attributed to their biodegradability and bioactive components released during in vivo degradation.

Conclusion: This review summarizes the current therapies accelerating bone formation in DO and the beneficial role of biometals in bone regeneration, particularly focusing on the use of biometal Mg and its alloy in promoting bone formation in DO. Translational potential: The potential clinical applications using Mg-based devices to accelerate DO are promising. Mg stimulates expression of multiple intrinsic biological factors and the development of Mg as an implantable component in DO may be used to argument bone formation and consolidation in DO.
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http://dx.doi.org/10.1016/j.jot.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859169PMC
March 2021

Alpha-Fetoprotein-Producing Lung Hepatoid Adenocarcinoma with Brain Metastasis Treated with S-1.

Case Rep Oncol 2020 Sep-Dec;13(3):1552-1559. Epub 2020 Dec 23.

Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.

Lung hepatoid adenocarcinoma (HAC) is a rare primary lung carcinoma pathologically characterized by hepatocellular carcinoma-like tumor cells, the majority of which produce alpha-fetoprotein (AFP). The clinical prognosis of lung HAC is generally poor, and effective therapeutic regimens for inoperable or recurrent cases have not been established. Here, we report a case of AFP-producing lung HAC with brain metastasis with long-term disease control, treated with the 5-fluorouracil-derived regimen S-1. The patient was a 66-year-old male admitted to the hospital with alexia. Chest X-ray revealed a massive tumor in the left upper lobe, and a head CT scan revealed a metastasis in the left parietal lobe. The laboratory data showed a remarkably elevated AFP level (97,561 ng/mL). Pathological assessment of the resected brain tumor revealed HAC, which was compatible with the lung biopsies. Together with the absence of other metastatic lesions, a final diagnosis of primary lung HAC, stage IV T4N3M1b, was given. The patient first underwent non-small cell lung cancer chemotherapy regimens (carboplatin and paclitaxel as the first line, and pemetrexed as the second line), but had clinical progression. After third-line oral S-1 (tegafur/gimeracil/oteracil) administration, the serum AFP level significantly dropped and the patient achieved long-term disease control without relapse, surviving more than 19 months after disease presentation. The autopsy result was consistent with the diagnosis of primary lung HAC, and immunohistochemical staining was AFP+, glypican 3+, and spalt-like transcription factor 4+. Here, we report the case of a rare primary lung HAC with apparent disease control on S-1 therapy, together with a literature review.
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http://dx.doi.org/10.1159/000511763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841735PMC
December 2020

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection.

medRxiv 2020 Nov 10. Epub 2020 Nov 10.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the COVID-19 pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 204 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 252 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼23% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but paradoxically these hCoV cross-reactive antibodies were boosted upon SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.11.06.20227215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668756PMC
November 2020

Deep Immune Profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.

medRxiv 2020 Sep 27. Epub 2020 Sep 27.

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8 T cells that correlated with use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct and implicate CD8 T cells in clinical presentation and trajectory of MIS-C.
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http://dx.doi.org/10.1101/2020.09.25.20201863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523167PMC
September 2020

Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications.

Science 2020 09 15;369(6508). Epub 2020 Jul 15.

Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.
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http://dx.doi.org/10.1126/science.abc8511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402624PMC
September 2020

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions.

bioRxiv 2020 May 23. Epub 2020 May 23.

Institute for Immunology, University of Pennsylvania Perelman School of Medicine.

COVID-19 has become a global pandemic. Immune dysregulation has been implicated, but immune responses remain poorly understood. We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of ~200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three "immunotypes" associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.
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http://dx.doi.org/10.1101/2020.05.20.106401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263500PMC
May 2020

CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy.

Blood Adv 2019 11;3(22):3539-3549

Division of Oncology, Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA; and.

Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell product targeting CD19 is approved for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the impact of pretreatment variables, such as CD19 expression level, on leukemic blasts, the presence of CD19- subpopulations, and especially prior CD19-targeted therapy, on the response to CAR T-cell therapy has not been determined. We analyzed 166 patients treated with CAR T-cell therapy at our institution. Eleven patients did not achieve a minimal residual disease (MRD)- deep remission, whereas 67 patients had a recurrence after achieving a MRD- deep remission: 28 patients with CD19+ leukemia and 39 patients with CD19- leukemia. Return of CD19+ leukemia was associated with loss of CAR T-cell function, whereas CD19- leukemia was associated with continued CAR T-cell function. There were no significant differences in efficacy of CAR T cells in CD19-dim B-ALL, compared with CD19-normal or -bright B-ALL. Consistent with this, CAR T cells recognized and lysed cells with very low levels of CD19 expression in vitro. The presence of dim CD19 or rare CD19- events by flow cytometry did not predict nonresponse or recurrence after CAR T-cell therapy. However, prior therapy with the CD19-directed, bispecific T-cell engager blinatumomab was associated with a significantly higher rate of failure to achieve MRD- remission or subsequent loss of remission with antigen escape. Finally, immunophenotypic heterogeneity and lineage plasticity were independent of underlying clonotype and cytogenetic abnormalities.
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http://dx.doi.org/10.1182/bloodadvances.2019000692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880911PMC
November 2019

Molecular Neuropathology in Practice: Clinical Profiling and Integrative Analysis of Molecular Alterations in Glioblastoma.

Acad Pathol 2019 Jan-Dec;6:2374289519848353. Epub 2019 May 27.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Molecular profiling of glioblastoma has revealed complex cytogenetic, epigenetic, and molecular abnormalities that are necessary for diagnosis, prognosis, and treatment. Our neuro-oncology group has developed a data-driven, institutional consensus guideline for efficient and optimal workup of glioblastomas based on our routine performance of molecular testing. We describe our institution's testing algorithm, assay development, and genetic findings in glioblastoma, to illustrate current practices and challenges in neuropathology related to molecular and genetic testing. We have found that coordination of test requisition, tissue handling, and incorporation of results into the final pathologic diagnosis by the neuropathologist improve patient care. Here, we present analysis of promoter methylation and next-generation sequencing results of 189 patients, obtained utilizing our internal processes led by the neuropathology team. Our institutional pathway for neuropathologist-driven molecular testing has streamlined the management of glioblastoma samples for efficient return of results for incorporation of genomic data into the pathological diagnosis and optimal patient care.
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http://dx.doi.org/10.1177/2374289519848353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537274PMC
May 2019

Differences in Genomic Profiles and Outcomes Between Thoracic and Adrenal Neuroblastoma.

J Natl Cancer Inst 2019 11;111(11):1192-1201

Background: Neuroblastoma is a biologically and clinically heterogeneous disease. Based on recent studies demonstrating an association between the primary tumor site, prognosis, and commonly measured tumor biological features, we hypothesized that neuroblastomas arising in different sites would show distinct genomic features reflective of the developmental biology of the sympathicoadrenal nervous system.

Methods: We first compared genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) compared to thoracic sympathetic ganglia (n = 118). We also evaluated association of common germline variation with these primary sites in 1027 European-American neuroblastoma patients.

Results: We observed higher rates of MYCN amplification, chromosome 1q gain, and chromosome 11q deletion among adrenal tumors, which were highly predictive of functional RNA signatures. Surprisingly, thoracic neuroblastomas were more likely to harbor ALK driver mutations than adrenal cases among all cases (odds ratio = 1.89, 95% confidence interval = 1.04 to 3.43), and among cases without MYCN amplification (odds ratio = 2.86, 95% confidence interval = 1.48 to 5.49). Common germline single nucleotide polymorphisms (SNPs) in BARD1 (previously associated with high-risk neuroblastoma) were found to be strongly associated with predisposition for origin at adrenal, rather than thoracic, sites.

Conclusions: Neuroblastomas arising in the adrenal gland are more likely to harbor structural DNA aberrations including MYCN amplification, whereas thoracic tumors show defects in mitotic checkpoints resulting in hyperdiploidy. Despite the general association of ALK mutations with high-risk disease, thoracic tumors are more likely to harbor gain-of-function ALK aberrations. Site of origin is likely reflective of stage of sympathetic nervous system development when malignant transformation occurs and is a surrogate for underlying tumor biology.
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http://dx.doi.org/10.1093/jnci/djz027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855946PMC
November 2019

Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.

PLoS Genet 2017 May 18;13(5):e1006787. Epub 2017 May 18.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.

Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16-1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21-1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis.
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http://dx.doi.org/10.1371/journal.pgen.1006787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456408PMC
May 2017

Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism.

Nature 2015 Dec 11;528(7582):418-21. Epub 2015 Nov 11.

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells. Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P = 7.47 × 10(-29), odds ratio 0.65, 95% confidence interval 0.60-0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P < 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells.
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http://dx.doi.org/10.1038/nature15540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775078PMC
December 2015

A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis.

Cancer Cell 2015 Nov 17;28(5):599-609. Epub 2015 Oct 17.

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

A more complete understanding of aberrant oncogenic signaling in neuroblastoma, a malignancy of the developing sympathetic nervous system, is paramount to improving patient outcomes. Recently, we identified LIN28B as an oncogenic driver in high-risk neuroblastoma. Here, we identify the oncogene RAN as a LIN28B target and show regional gain of chromosome 12q24 as an additional somatic alteration resulting in increased RAN expression. We show that LIN28B influences RAN expression by promoting RAN Binding Protein 2 expression and by directly binding RAN mRNA. Further, we demonstrate a convergence of LIN28B and RAN signaling on Aurora kinase A activity. Collectively, these findings demonstrate that LIN28B-RAN-AURKA signaling drives neuroblastoma oncogenesis, suggesting that this pathway may be amenable to therapeutic targeting.
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http://dx.doi.org/10.1016/j.ccell.2015.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643330PMC
November 2015

Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

Nat Genet 2015 08 29;47(8):864-71. Epub 2015 Jun 29.

1] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [3] Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.
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http://dx.doi.org/10.1038/ng.3333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775079PMC
August 2015

CASC15-S Is a Tumor Suppressor lncRNA at the 6p22 Neuroblastoma Susceptibility Locus.

Cancer Res 2015 Aug 22;75(15):3155-66. Epub 2015 Jun 22.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Chromosome 6p22 was identified recently as a neuroblastoma susceptibility locus, but its mechanistic contributions to tumorigenesis are as yet undefined. Here we report that the most highly significant single-nucleotide polymorphism (SNP) associations reside within CASC15, a long noncoding RNA that we define as a tumor suppressor at 6p22. Low-level expression of a short CASC15 isoform (CASC15-S) associated highly with advanced neuroblastoma and poor patient survival. In human neuroblastoma cells, attenuating CASC15-S increased cellular growth and migratory capacity. Gene expression analysis revealed downregulation of neuroblastoma-specific markers in cells with attenuated CASC15-S, with concomitant increases in cell adhesion and extracellular matrix transcripts. Altogether, our results point to CASC15-S as a mediator of neural growth and differentiation, which impacts neuroblastoma initiation and progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-3613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526355PMC
August 2015

CODEX: a normalization and copy number variation detection method for whole exome sequencing.

Nucleic Acids Res 2015 Mar 23;43(6):e39. Epub 2015 Jan 23.

Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA

High-throughput sequencing of DNA coding regions has become a common way of assaying genomic variation in the study of human diseases. Copy number variation (CNV) is an important type of genomic variation, but detecting and characterizing CNV from exome sequencing is challenging due to the high level of biases and artifacts. We propose CODEX, a normalization and CNV calling procedure for whole exome sequencing data. The Poisson latent factor model in CODEX includes terms that specifically remove biases due to GC content, exon capture and amplification efficiency, and latent systemic artifacts. CODEX also includes a Poisson likelihood-based recursive segmentation procedure that explicitly models the count-based exome sequencing data. CODEX is compared to existing methods on a population analysis of HapMap samples from the 1000 Genomes Project, and shown to be more accurate on three microarray-based validation data sets. We further evaluate performance on 222 neuroblastoma samples with matched normals and focus on a well-studied rare somatic CNV within the ATRX gene. We show that the cross-sample normalization procedure of CODEX removes more noise than normalizing the tumor against the matched normal and that the segmentation procedure performs well in detecting CNVs with nested structures.
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http://dx.doi.org/10.1093/nar/gku1363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381046PMC
March 2015

Rare variants in TP53 and susceptibility to neuroblastoma.

J Natl Cancer Inst 2014 Apr 14;106(4):dju047. Epub 2014 Mar 14.

Affiliations of authors: Division of Oncology (SJD, MDi, DAO, KC, KRB, MRR, JMM), Center for Childhood Cancer Research (SJD, MDi, DAO, KC, KRB, MRR, JMM), Center for Applied Genomics (HH), and Division of Genetics (HH, MDe) Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics (SJD, DAO, KRB, HH, MDe, JMM), Abramson Cancer Center (SJD, JMM), Genomics and Computational Biology, Biomedical Graduate Studies (SJD, DAO, JMM), and Department of Biostatistics and Epidemiology (MDe), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (SJD, HH, MDe, JMM); Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy (MC, AI); Ceinge-Biotecnologie Avanzate, Naples, Italy (MC, AI); University of Rome "La Sapienza," Department of Molecular Medicine, Rome, Italy (MDe).

TP53 is the most frequently mutated gene in human malignancies; however, de novo somatic mutations in childhood embryonal cancers such as neuroblastoma are rare. We report on the analysis of three independent case-control cohorts comprising 10290 individuals and demonstrate that rs78378222 and rs35850753, rare germline variants in linkage disequilibrium that map to the 3' untranslated region (UTR) of TP53 and 5' UTR of the Δ133 isoform of TP53, respectively, are robustly associated with neuroblastoma (rs35850753: odds ratio [OR] = 2.7, 95% confidence interval [CI] = 2.0 to 3.6, P combined = 3.43×10(-12); rs78378222: OR = 2.3, 95% CI = 1.8 to 2.9, P combined = 2.03×10(-11)). All statistical tests were two-sided. These findings add neuroblastoma to the complex repertoire of human cancers influenced by the rs78378222 hypomorphic allele, which impairs proper termination and polyadenylation of TP53 transcripts. Future studies using whole-genome sequencing data are likely to reveal additional rare variants with large effect sizes contributing to neuroblastoma tumorigenesis.
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http://dx.doi.org/10.1093/jnci/dju047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982892PMC
April 2014

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk.

Proc Natl Acad Sci U S A 2012 Apr 10;109(17):6686-91. Epub 2012 Apr 10.

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

Copy number variants (CNVs) are a recently recognized class of human germ line polymorphisms and are associated with a variety of human diseases, including cancer. Because of the strong genetic influence on prostate cancer, we sought to identify functionally active CNVs associated with susceptibility of this cancer type. We queried low-frequency biallelic CNVs from 1,903 men of Caucasian origin enrolled in the Tyrol Prostate Specific Antigen Screening Cohort and discovered two CNVs strongly associated with prostate cancer risk. The first risk locus (P = 7.7 × 10(-4), odds ratio = 2.78) maps to 15q21.3 and overlaps a noncoding enhancer element that contains multiple activator protein 1 (AP-1) transcription factor binding sites. Chromosome conformation capture (Hi-C) data suggested direct cis-interactions with distant genes. The second risk locus (P = 2.6 × 10(-3), odds ratio = 4.8) maps to the α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase C (MGAT4C) gene on 12q21.31. In vitro cell-line assays found this gene to significantly modulate cell proliferation and migration in both benign and cancer prostate cells. Furthermore, MGAT4C was significantly overexpressed in metastatic versus localized prostate cancer. These two risk associations were replicated in an independent PSA-screened cohort of 800 men (15q21.3, combined P = 0.006; 12q21.31, combined P = 0.026). These findings establish noncoding and coding germ line CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression.
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http://dx.doi.org/10.1073/pnas.1117405109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340033PMC
April 2012

Optimizing copy number variation analysis using genome-wide short sequence oligonucleotide arrays.

Nucleic Acids Res 2010 Jun 15;38(10):3275-86. Epub 2010 Feb 15.

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, NY 10065, USA.

The detection of copy number variants (CNV) by array-based platforms provides valuable insight into understanding human diversity. However, suboptimal study design and data processing negatively affect CNV assessment. We quantitatively evaluate their impact when short-sequence oligonucleotide arrays are applied (Affymetrix Genome-Wide Human SNP Array 6.0) by evaluating 42 HapMap samples for CNV detection. Several processing and segmentation strategies are implemented, and results are compared to CNV assessment obtained using an oligonucleotide array CGH platform designed to query CNVs at high resolution (Agilent). We quantitatively demonstrate that different reference models (e.g. single versus pooled sample reference) used to detect CNVs are a major source of inter-platform discrepancy (up to 30%) and that CNVs residing within segmental duplication regions (higher reference copy number) are significantly harder to detect (P < 0.0001). After adjusting Affymetrix data to mimic the Agilent experimental design (reference sample effect), we applied several common segmentation approaches and evaluated differential sensitivity and specificity for CNV detection, ranging 39-77% and 86-100% for non-segmental duplication regions, respectively, and 18-55% and 39-77% for segmental duplications. Our results are relevant to any array-based CNV study and provide guidelines to optimize performance based on study-specific objectives.
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http://dx.doi.org/10.1093/nar/gkq073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879534PMC
June 2010

The global regulator Ler is necessary for enteropathogenic Escherichia coli colonization of Caenorhabditis elegans.

Infect Immun 2006 Jan;74(1):64-72

Biology Department, Reed College, 3203 S.E. Woodstock Blvd., Portland, OR 97202, USA.

Enteropathogenic Escherichia coli (EPEC) is an important cause of infant diarrhea in developing countries and is useful for general investigations of the bacterial infection process. However, the study of the molecular pathogenesis of EPEC has been hampered by the lack of genetically tractable, convenient animal models. We have therefore developed the use of the nematode Caenorhabditis elegans as a small animal model of infection for this diarrheal pathogen. We found that nematodes died faster on nematode growth medium in the presence of EPEC pathogens than in the presence of the laboratory control strain MG1655. Increased numbers of pathogens in the gut, determined by standard plate count assays and fluorescence microscopy using green fluorescent protein-expressing bacteria, correlated with killing. Deletion of the gene encoding the global regulator Ler severely reduced the ability of EPEC to colonize the nematode gut and could be complemented by providing the ler gene on a multicopy plasmid in trans. Neither the type III secretion system nor the type IV bundle-forming pilus was required for colonization. Combined, the similarities and distinct differences between EPEC infection of nematodes and that of humans offer a unique opportunity to study several stages of the infection process, namely, attachment, colonization, and persistence, in a genetically tractable, inexpensive, and convenient in vivo system.
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http://dx.doi.org/10.1128/IAI.74.1.64-72.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1346621PMC
January 2006