Publications by authors named "Elaine R Mardis"

294 Publications

Association of 17q22 Amplicon Via Cell-Free DNA With Platinum Chemotherapy Response in Metastatic Triple-Negative Breast Cancer.

JCO Precis Oncol 2021 24;5. Epub 2021 Nov 24.

Division of Medical Oncology, The Ohio State University College of Medicine, Columbus, OH.

Purpose: To determine whether specific somatic copy-number alterations detectable in circulating tumor DNA (ctDNA) from patients with metastatic triple-negative breast cancer (mTNBC) are associated with sensitivity to platinum chemotherapy.

Materials And Methods: In this secondary analysis of a large cohort of patients with mTNBC whose ctDNA underwent ultralow-pass whole-genome sequencing, tumor fraction and somatic copy-number alterations were derived with the ichorCNA algorithm. Seventy-two patients were identified who had received a platinum-based chemotherapy regimen in the metastatic setting. Gene-level copy-number analyses were performed with GISTIC2.0. Cytobands were associated with progression-free survival (PFS) to platinum chemotherapy using Cox proportional hazards models. The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium data sets were interrogated for frequency of significant cytobands in primary triple-negative breast cancer (pTNBC) tumors.

Results: Among 71 evaluable patients, 17q21 and 17q22 amplifications were most strongly associated with improved PFS with platinum chemotherapy. There were no significant differences in clinicopathologic features or (neo)adjuvant chemotherapy among patients with 17q22 amplification. Patients with 17q22 amplification (n = 17) had longer median PFS with platinum (7.0 3.8 months; log-rank = .015) than patients without 17q22 amplification (n = 54), an effect that remained significant in multivariable analyses (PFS hazard ratio 0.37; 95% CI, 0.16 to 0.84; = .02). Among 39 patients who received the nonplatinum chemotherapy agent capecitabine, there was no association between 17q22 amplification and capecitabine PFS (log-rank = .69). In The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium, 17q22 amplification occurred in more than 20% of both pTNBC and mTNBC tumors, whereas 17q21 was more frequently amplified in mTNBC relative to pTNBC (16% 8.1%, = .015).

Conclusion: The 17q22 amplicon, detected by ctDNA, is associated with improved PFS with platinum chemotherapy in patients with mTNBC and warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.21.00104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624042PMC
November 2021

Molecular and pathology features of colorectal tumors and patient outcomes are associated with Fusobacterium nucleatum and its subspecies animalis.

Cancer Epidemiol Biomarkers Prev 2021 Nov 4. Epub 2021 Nov 4.

Population Science, American Cancer Society.

Background: Fusobacterium nucleatum activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis.

Methods: We characterized F nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer (CRC) specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 CRC patients and assessed associations between F nucleatum presence and clinical characteristics, CRC-specific mortality, and somatic mutations.

Results: F nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors-particularly subspecies animalis. Presence of F nucleatum was associated with higher CRC-specific mortality (hazard ratio [HR], 1.97; P=0.0004). This association was restricted to non-hypermutated, microsatellite-stable tumors (HR, 2.13; P=0.0002) and those who received chemotherapy (HR = 1.92, CI: 1.07-3.45, p-value = 0.029). Only F nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with CRC-specific mortality (HR, 2.16; P=0.0016)-subspecies vincentii and nucleatum were not (HR, 1.07, P=0.86). Additional adjustment for tumor stage suggests that the effect of F nucleatum on mortality is partly driven by a stage shift. Presence of F nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, ERBB3 mutations, and suggestively associated with TP53 mutations.

Conclusions: F nucleatum, and particularly subspecies animalis, was associated with a higher CRC-specific mortality and specific somatic mutated genes.

Impact: Our findings identify the F nucleatum subspecies animalis as negatively impacting CRC mortality which may occur through a stage shift and its effect on chemoresistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-21-0463DOI Listing
November 2021

Causal and Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency.

J Clin Endocrinol Metab 2021 Oct 26. Epub 2021 Oct 26.

Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, UT, USA.

Context: A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI).

Objective: We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI.

Design: The study was an observational study.

Setting: Subjects were recruited at academic institutions.

Patients: Subjects from Boston (n=98), the NIH and Washington University (n=98), Pittsburgh (n=20), Italy (n=43) and France (n=32) were diagnosed with POI (amenorrhea with an elevated FSH level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n=233).

Intervention: We performed whole exome sequencing (WES) and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model.

Main Outcome: Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified.

Results: Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1 and BOD1L1).

Conclusions: Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab775DOI Listing
October 2021

Somatic Variation as an Incidental Finding in the Pediatric Next Generation Sequencing Era.

Cold Spring Harb Mol Case Stud 2021 Oct 29. Epub 2021 Oct 29.

The Steve and Cindy Rasmussen Inst for Genomic Medicine, Nationwide Children's Hospital; Dept of Pathology, The Ohio State University; Dept of Pediatrics, The Ohio State University

The methodologic approach used in next-generation sequencing (NGS) affords a high depth of coverage in genomic analysis. Inherent in the nature of genomic testing, there exists potential for identifying genomic findings that are incidental or secondary to the indication for clinical testing, with the frequency dependent on the breadth of analysis and the tissue sample under study. The interpretation and management of clinically meaningful incidental genomic findings is a pressing issue particularly in the pediatric population. Our study describes a 16-month old male who presented with Dandy-Walker malformation, metopic craniosynostosis and developmental delay. Clinical exome sequencing (ES) trio analysis revealed the presence of two variants in the proband. The first was a de novo variant in the PPP2R1A gene (c.773G>A, p.Arg258His), which is associated with autosomal dominant (AD) intellectual disability, accounting for the proband's clinical phenotype. The second was a recurrent hotspot variant in the CBL gene (c.1111T>C, p.Tyr371His), which was present at a variant allele fraction of 11%, consistent with somatic variation in the peripheral blood sample. Germline pathogenic variants in CBL are associated with AD Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (JMML). Molecular analyses using a different tissue source, buccal epithelial cells, suggest that the CBL alteration may represent a clonal population of cells restricted to leukocytes. This report highlights the laboratory methodologic and interpretative processes and clinical considerations in the setting of acquired variation detected during clinical ES in a pediatric patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a006135DOI Listing
October 2021

Targeted Therapy in a Young Adult With a Novel Epithelioid Tumor Driven by a PRRC2B-ALK Fusion.

J Natl Compr Canc Netw 2021 10 15;19(10):1116-1121. Epub 2021 Oct 15.

Department of Hematology/Oncology/BMT, Division of Pediatrics, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio.

This case report describes an 18-year-old woman with an unusual epithelioid tumor of the omentum with a novel PRRC2B-ALK fusion. Although the atypical pathologic features raised significant diagnostic challenges, expression of CD30 on tumor cells and detection of an ALK rearrangement provided critical information for selecting targeted therapy in a patient not suitable for surgical resection. Despite an initially promising therapeutic response, the patient died. The efficacy of treatment was confirmed by the lack of viable tumor cells at autopsy. This case highlights the role of timely targeted therapy in patients with rare tumors and novel actionable molecular targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2021.7056DOI Listing
October 2021

Characterization of the Genomic and Immunological Diversity of Malignant Brain Tumors Through Multi-Sector Analysis.

Cancer Discov 2021 Oct 5. Epub 2021 Oct 5.

Department of Neurological Surgery, Washington University in St. Louis School of Medicine

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). While the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer-cell intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole exome, RNA, and TCR-sequencing. Our analyses identified differences between primary and secondary malignancies with gliomas displaying more spatial heterogeneity at the genomic and neoantigen level. Additionally, this spatial diversity was recapitulated in the distribution of T cell clones where some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-21-0291DOI Listing
October 2021

Defining the AHR-regulated transcriptome in NK cells reveals gene expression programs relevant to development and function.

Blood Adv 2021 11;5(22):4605-4618

Cellular Therapy and Cancer Immunotherapy Program.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular processes in cancer and immunity, including innate immune cell development and effector function. However, the transcriptional repertoire through which AHR mediates these effects remains largely unexplored. To elucidate the transcriptional elements directly regulated by AHR in natural killer (NK) cells, we performed RNA and chromatin immunoprecipitation sequencing on NK cells exposed to AHR agonist or antagonist. We show that mature peripheral blood NK cells lack AHR, but its expression is induced by Stat3 during interleukin-21-driven activation and proliferation, coincident with increased NCAM1 (CD56) expression resulting in a CD56bright phenotype. Compared with control conditions, NK cells expanded in the presence of the AHR antagonist, StemRegenin-1, were unaffected in proliferation or cytotoxicity, had no increase in NCAM1 transcription, and maintained the CD56dim phenotype. However, it showed altered expression of 1004 genes including those strongly associated with signaling pathways. In contrast, NK cells expanded in the presence of the AHR agonist, kynurenine, showed decreased cytotoxicity and altered expression of 97 genes including those strongly associated with oxidative stress and cellular metabolism. By overlaying these differentially expressed genes with AHR chromatin binding, we identified 160 genes directly regulated by AHR, including hallmark AHR targets AHRR and CYP1B1 and known regulators of phenotype, development, metabolism, and function such as NCAM1, KIT, NQO1, and TXN. In summary, we define the AHR transcriptome in NK cells, propose a model of AHR and Stat3 coregulation, and identify potential pathways that may be targeted to overcome AHR-mediated immune suppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004533DOI Listing
November 2021

Germline BAP1 Mutation in a Family With Multi-Generational Meningioma With Rhabdoid Features: A Case Series and Literature Review.

Front Oncol 2021 24;11:721712. Epub 2021 Aug 24.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, United States.

Meningioma is the most common primary brain tumor, and recurrence risk increases with increasing WHO Grade from I to III. Rhabdoid meningiomas are a subset of WHO Grade III tumors with rhabdoid cells, a high proliferation index, and other malignant features that follow an aggressive clinical course. Some meningiomas with rhabdoid features either only focally or without other malignant features are classified as lower grade yet still recur early. Recently, inactivating mutations in the tumor suppressor gene have been associated with poorer prognosis in rhabdoid meningioma and meningioma with rhabdoid features, and germline mutations have been linked to a hereditary tumor predisposition syndrome (TPDS) predisposing patients primarily to melanoma and mesothelioma. We present the first report of a familial inactivating mutation identified after multiple generations of a family presented with meningiomas with rhabdoid features instead of with previously described loss-associated malignancies. A 24-year-old female presented with a Grade II meningioma with rhabdoid and papillary features treated with subtotal resection, adjuvant external beam radiation therapy, and salvage gamma knife radiosurgery six years later. Around that time, her mother presented with a meningioma with rhabdoid and papillary features managed with resection and adjuvant radiation therapy. Germline testing was positive for a pathogenic mutation in both patients. Sequencing of both tumors demonstrated biallelic inactivation the combination of germline mutation and either loss of heterozygosity or somatic mutation. No additional mutations implicated in oncogenesis were noted from either patient's germline or tumor sequencing, suggesting that the inactivation of was responsible for pathogenesis. These cases demonstrate the importance of routine tumor testing in meningioma with rhabdoid features regardless of grade, germline testing for patients with inactivated tumors, and tailored cancer screening in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.721712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421801PMC
August 2021

Endogenous retrovirus envelope as a tumor-associated immunotherapeutic target in murine osteosarcoma.

iScience 2021 Jul 19;24(7):102759. Epub 2021 Jun 19.

Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, 700 Children's Drive Columbus, OH 43205, USA.

Osteosarcoma remains one of the deadliest cancers in pediatrics and young adults. We administered two types of immunotherapies, oncolytic virotherapy and immune checkpoint inhibition, to two murine osteosarcoma models and observed divergent results. Mice bearing F420 showed no response, whereas those with K7M2 showed prolonged survival in response to combination therapy. K7M2 had higher expression of immune-related genes and higher baseline immune cell infiltrates, but there were no significant differences in tumor mutational burden or predicted MHC class I binding of nonsynonymous mutations. Instead, we found several mouse endogenous retrovirus sequences highly expressed in K7M2 compared with F420. T cell tetramer staining for one of them, gp70, was detected in mice with K7M2 but not F420, suggesting that endogenous retrovirus proteins are targets for the anti-tumor immune reaction. Given prior observations of endogenous retrovirus expression in human osteosarcomas, our findings may be translatable to human disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267546PMC
July 2021

PTEN somatic mutations contribute to spectrum of cerebral overgrowth.

Brain 2021 Nov;144(10):2971-2978

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.

Phosphatase and tensin homologue (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signalling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the paediatric population. Here we report two somatic variants of PTEN affecting a single patient presenting with intractable epilepsy and hemimegalencephaly that varied in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis of affected brain tissue identified two somatic variants in PTEN. The first variant was present in multiple cell lineages throughout the entire hemisphere and associated with mild cerebral overgrowth. The second variant was restricted to posterior brain regions and affected the opposite PTEN allele, resulting in a segmental region of more severe malformation, and the only neurons in which it was found by single-nuclei RNA-sequencing had a unique disease-related expression profile. This study reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and furthermore demonstrates the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab173DOI Listing
November 2021

Gastroblastoma with a novel EWSR1-CTBP1 fusion presenting in adolescence.

Genes Chromosomes Cancer 2021 Sep 7;60(9):640-646. Epub 2021 Jun 7.

Department of Pathology, The Ohio State University, Columbus, Ohio, USA.

Gastroblastomas are rare tumors with a biphasic epithelioid/spindle cell morphology that typically present in early adulthood and have recurrent MALAT1-GLI1 fusions. We describe an adolescent patient with Wiskott-Aldrich syndrome who presented with a large submucosal gastric tumor with biphasic morphology. Despite histologic features consistent with gastroblastoma, a MALAT1-GLI1 fusion was not found in this patient's tumor; instead, comprehensive molecular profiling identified a novel EWSR1-CTBP1 fusion and no other significant genetic alterations. The tumor also overexpressed NOTCH and FGFR by RNA profiling. The novel fusion and expression profile suggest a role for epithelial-mesenchymal transition in this tumor, with potential implications for the pathogenesis of biphasic gastric tumors such as gastroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22973DOI Listing
September 2021

Genomic prediction of neoantigens: immunogenomics before NGS.

Authors:
Elaine R Mardis

Nat Rev Genet 2021 09;22(9):550-551

Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41576-021-00374-4DOI Listing
September 2021

Novel morphologic findings in PLAG1-rearranged soft tissue tumors.

Genes Chromosomes Cancer 2021 Aug 29;60(8):577-585. Epub 2021 Apr 29.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

Oncogenesis in PLAG1-rearranged tumors often results from PLAG1 transcription factor overexpression driven by promoter-swapping between constitutively expressed fusion partners. PLAG1-rearranged tumors demonstrate diverse morphologies. This study adds to this morphologic heterogeneity by introducing two tumors with PLAG1 rearrangements that display distinct histologic features. The first arose in the inguinal region of a 3-year-old, appeared well-circumscribed with a multinodular pattern, and harbored two fusions: ZFHX4-PLAG1 and CHCHD7-PLAG1. The second arose in the pelvic cavity of a 15-year-old girl, was extensively infiltrative and vascularized with an adipocytic component, and demonstrated a COL3A1-PLAG1 fusion. Both showed low-grade cytomorphology, scarce mitoses, no necrosis, and expression of CD34 and desmin. The ZFHX4-/CHCHD7-PLAG1-rearranged tumor showed no evidence of recurrence after 5 months. By contrast, the COL3A1-PLAG1-rearranged tumor quickly recurred following primary excision with positive margins; subsequent re-excision with adjuvant chemotherapy resulted in no evidence of recurrence after 2 years. While both tumors show overlap with benign and malignant fibroblastic and fibrovascular neoplasms, they also display divergent features. These cases highlight the importance of appropriate characterization in soft tissue tumors with unusual clinical and histologic characteristics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22953DOI Listing
August 2021

Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma.

Acta Neuropathol Commun 2021 04 7;9(1):61. Epub 2021 Apr 7.

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute At Nationwide Children's Hospital, 575 Children's Crossroad, Columbus, OH, 43215 , USA.

Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1. Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1. These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-021-01164-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025529PMC
April 2021

Clinical response to dabrafenib plus trametinib in a pediatric ganglioglioma with p.T599dup mutation.

Cold Spring Harb Mol Case Stud 2021 04 8;7(2). Epub 2021 Apr 8.

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43215, USA.

In this follow-up report, we present updated information regarding a previously reported pediatric patient with a World Health Organization grade I ganglioglioma harboring a p.T599dup mutation ( 4: a002618). This patient, based on our initial finding, is receiving combination targeted therapy with a selective BRAF inhibitor (dabrafenib) plus MEK inhibitor (trametinib). The combination therapy was started after the patient experienced progressive tumor growth and worsening neurological symptoms, including visual changes, headaches, and peripheral neuropathy, despite 9 months of treatment with adjuvant chemotherapy (vinblastine). The patient has been receiving dabrafenib plus trametinib for 15 months and continues to have stable disease as well as improved neurological symptoms. Although combinatorial therapy targeting BRAF and MEK using dabrafenib and trametinib, respectively, is indicated for tumors harboring a p.V600E/K mutation, our report demonstrates efficacy of this combination in a non-V600E -mutated tumor. The identification of alterations may assist clinicians in determining alternative targeted treatment strategies, especially considering the paucity of effective treatments for primary brain tumors and the poor prognosis associated with many central nervous system (CNS) diagnoses. Additional case studies or larger cohort reports will continue to clarify the efficacy of BRAF and/or MEK inhibitors in patients whose tumors harbor a alteration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a006023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040738PMC
April 2021

Frontiers in cancer immunotherapy-a symposium report.

Ann N Y Acad Sci 2021 04 13;1489(1):30-47. Epub 2020 Nov 13.

Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, California.

Cancer immunotherapy has dramatically changed the approach to cancer treatment. The aim of targeting the immune system to recognize and destroy cancer cells has afforded many patients the prospect of achieving deep, long-term remission and potential cures. However, many challenges remain for achieving the goal of effective immunotherapy for all cancer patients. Checkpoint inhibitors have been able to achieve long-term responses in a minority of patients, yet improving response rates with combination therapies increases the possibility of toxicity. Chimeric antigen receptor T cells have demonstrated high response rates in hematological cancers, although most patients experience relapse. In addition, some cancers are notoriously immunologically "cold" and typically are not effective targets for immunotherapy. Overcoming these obstacles will require new strategies to improve upon the efficacy of current agents, identify biomarkers to select appropriate therapies, and discover new modalities to expand the accessibility of immunotherapy to additional tumor types and patient populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nyas.14526DOI Listing
April 2021

YAP1-FAM118B Fusion Defines a Rare Subset of Childhood and Young Adulthood Meningiomas.

Am J Surg Pathol 2021 03;45(3):329-340

The Steve and Cindy Rasmussen Institute for Genomic Medicine.

Meningiomas are a central nervous system tumor primarily afflicting adults, with <1% of cases diagnosed during childhood or adolescence. Somatic variation in NF2 may be found in ∼50% of meningiomas, with other genetic drivers (eg, SMO, AKT1, TRAF7) contributing to NF2 wild-type tumors. NF2 is an upstream negative regulator of YAP signaling and loss of the NF2 protein product, Merlin, results in YAP overexpression and target gene transcription. This mechanism of dysregulation is described in NF2-driven meningiomas, but further work is necessary to understand the NF2-independent mechanism of tumorigenesis. Amid our institutional patient-centric comprehensive molecular profiling study, we identified an individual with meningioma harboring a YAP1-FAM118B fusion, previously reported only in supratentorial ependymoma. The tumor histopathology was remarkable, characterized by prominent islands of calcifying fibrous nodules within an overall collagen-rich matrix. To gain insight into this finding, we subsequently evaluated the genetic landscape of 11 additional pediatric and adolescent/young adulthood meningioma patients within the Children's Brain Tumor Tissue Consortium. A second individual harboring a YAP1-FAM118B gene fusion was identified within this database. Transcriptomic profiling suggested that YAP1-fusion meningiomas are biologically distinct from NF2-driven meningiomas. Similar to other meningiomas, however, YAP1-fusion meningiomas demonstrated overexpression of EGFR and MET. DNA methylation profiling further distinguished YAP1-fusion meningiomas from those observed in ependymomas. In summary, we expand the genetic spectrum of somatic alteration associated with NF2 wild-type meningioma to include the YAP1-FAM118B fusion and provide support for aberrant signaling pathways potentially targetable by therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001597DOI Listing
March 2021

Infantile fibrosarcoma-like tumor driven by novel fusion consolidated with cabozantinib.

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

Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.

Infantile fibrosarcoma (IFS) is nearly universally driven by gene fusions involving the NTRK family. fusions account for ∼85% of alterations; the remainder are attributed to NTRK-variant fusions. Rarely, other genomic aberrations have been described in association with tumors identified as IFS or IFS-like. We describe the utility of genomic characterization of an IFS-like tumor. We also describe the successful treatment combination of VAC (vincristine, actinomycin, cyclophosphamide) with tyrosine kinase inhibitor (TKI) maintenance in this entity. This patient presented at birth with a right facial mass, enlarging at 1 mo to 4.9 × 4.5 × 6.3 cm. Biopsy demonstrated hypercellular fascicles of spindle cells with patchy positivity for smooth muscle actin (SMA) and negativity for S100, desmin, myogenin, and MyoD1. Targeted RNA sequencing identified a novel fusion with confirmed absence of , and the patient was diagnosed with an IFS-like tumor. A positron emission tomography (PET) scan was negative for metastatic disease. VAC was given for a duration of 10 mo. Resection at 13 mo of age demonstrated positive margins. Cabozantinib, a MET-targeting TKI, was initiated. The patient tolerated cabozantinib well and has no evidence of disease at 24 mo of age. We describe a novel driver fusion in association with a locally aggressive IFS-like tumor. MET functions as an oncogene and, when associated with the RNA binding protein RBPMS, forms an in-frame fusion product that retains the MET kinase domain. This fusion is associated with aberrant cell signaling pathway expression and subsequent malignancy. We describe treatment with cabozantinib in a patient with an IFS-like neoplasm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a005645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552925PMC
October 2020

Genetic Characterization of Pediatric Sarcomas by Targeted RNA Sequencing.

J Mol Diagn 2020 10 1;22(10):1238-1245. Epub 2020 Aug 1.

Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, Ohio. Electronic address:

Somatic variants, primarily fusion genes and single-nucleotide variants (SNVs) or insertions/deletions (indels), are prevalent among sarcomas. In many cases, accurate diagnosis of these tumors incorporates genetic findings that may also carry prognostic or therapeutic significance. Using the anchored multiplex PCR-based FusionPlex system, a custom RNA sequencing panel was developed that simultaneously detects fusion genes, SNVs, and indels in 112 genes found to be recurrently mutated in solid tumors. Using this assay, a retrospective analysis was conducted to identify somatic variants that may have assisted with classifying a cohort of 90 previously uncharacterized primarily pediatric sarcoma specimens. In total, somatic variants were identified in 45.5% (41/90) of the samples tested, including 22 cases with fusion genes and 19 cases with SNVs or indels. In addition, two of these findings represent novel alterations: a WHSC1L1/NCOA2 fusion and a novel in-frame deletion in the NRAS gene (NM_002524: c.174_176delAGC p.Ala59del). These sequencing results, taken in context with the available clinical data, indicate a potential change in the initial diagnosis, prognosis, or management in 27 of the 90 cases. This study presents a custom RNA sequencing assay that detects fusion genes and SNVs in tandem and has the ability to identify novel fusion partners. These features highlight the advantages associated with utilizing anchored multiplex PCR technology for the rapid and highly sensitive detection of somatic variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538815PMC
October 2020

Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival.

Nat Commun 2020 07 20;11(1):3644. Epub 2020 Jul 20.

Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, 90089, USA.

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17386-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371703PMC
July 2020

Somatic mosaicism correlates with clinical findings in epilepsy brain tissue.

Neurol Genet 2020 Aug 17;6(4):e460. Epub 2020 Jun 17.

The Steve and Cindy Rasmussen Institute for Genomic Medicine (K.E.M., D.C.K., K.M.S., T.A.B., E.C., K.L., V.M., H.Z., P.B., J.B., J.F., N.B., A.R.M., C.E.C., P.W., R.K.W., E.R.M.), Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH; Division of Genetic and Genomic Medicine (E.C.), Nationwide Children's Hospital, Columbus, OH; Department of Neurosurgery (A.S., J.L., J.A.P.), Nationwide Children's Hospital, Columbus, OH; Department of Pathology and Laboratory Medicine (C.R.P.), Nationwide Children's Hospital, Columbus, OH; Division of Child Neurology (A.P.O.), Nationwide Children's Hospital, Columbus, OH; Department of Radiology (J.A.R., S.H.S), Nationwide Children's Hospital, Columbus, OH; Department of Pediatrics (D.C.K., V.M., C.E.C., J.L., P.W., R.K.W, E.R.M., A.P.O.), The Ohio State University College of Medicine, Columbus, OH; Department of Neurosurgery (J.L., J.A.P., A.P.O.), The Ohio State University College of Medicine, Columbus, OH; Department of Pathology (C.E.C., C.R.P.), The Ohio State University College of Medicine, Columbus, OH; and Department of Biomedical Education & Anatomy (C.R.P.), Division of Anatomy, The Ohio State University College of Medicine, Columbus, OH.

Objective: Many genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic etiology in epilepsy and aim to discover somatic alterations in epilepsy-affected brain tissue.

Methods: We have pursued a research study to identify brain somatic mosaicism, using next-generation sequencing (NGS) technologies, in patients with treatment refractory epilepsy who have undergone surgical resection of affected brain tissue.

Results: We used an integrated combination of NGS techniques and conventional approaches (radiology, histopathology, and electrophysiology) to comprehensively characterize multiple brain regions from a single patient with intractable epilepsy. We present a 3-year-old male patient with West syndrome and intractable tonic seizures in whom we identified a pathogenic frameshift somatic variant in , present at a range of variant allele fractions (4.2%-19.5%) in 12 different brain tissues detected by targeted sequencing. The proportion of the variant correlated with severity and location of neurophysiology and neuroimaging abnormalities for each tissue.

Conclusions: Our findings support the importance of tissue-based sequencing and highlight a correlation in our patient between variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323482PMC
August 2020

The clonal evolution of metastatic colorectal cancer.

Sci Adv 2020 Jun 10;6(24):eaay9691. Epub 2020 Jun 10.

The Alvin J. Siteman Comprehensive Cancer Center, Washington University in St. Louis, St. Louis, MO, USA.

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aay9691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286679PMC
June 2020

Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.

Cold Spring Harb Mol Case Stud 2020 06 12;6(3). Epub 2020 Jun 12.

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.

Exome sequencing (ES) has become an important tool in pediatric genomic medicine, improving identification of disease-associated variation due to assay breadth. Depth is also afforded by ES, enabling detection of lower-frequency mosaic variation compared to Sanger sequencing in the studied tissue, thus enhancing diagnostic yield. Within a pediatric tertiary-care hospital, we report two years of clinical ES data from probands evaluated for genetic disease to assess diagnostic yield, characteristics of causal variants, and prevalence of mosaicism among disease-causing variants. Exome-derived, phenotype-driven variant data from 357 probands was analyzed concurrent with parental ES data, when available. Blood was the source of nucleic acid. Sequence read alignments were manually reviewed for all assessed variants. Sanger sequencing was used for suspected de novo or mosaic variation. Clinical provider notes were reviewed to determine concordance between laboratory-reported data and the ordering provider's interpretation of variant-associated disease causality. Laboratory-derived diagnostic yield and provider-substantiated diagnoses had 91.4% concordance. The cohort returned 117 provider-substantiated diagnoses among 115 probands for a diagnostic yield of 32.2%. De novo variants represented 64.9% of disease-associated variation within trio analyses. Among the 115 probands, five harbored disease-associated somatic mosaic variation. Two additional probands were observed to inherit a disease-associated variant from an unaffected mosaic parent. Among inheritance patterns, de novo variation was the most frequent disease etiology. Somatic mosaicism is increasingly recognized as a significant contributor to genetic disease, particularly with increased sequence depth attainable from ES. This report highlights the potential and importance of detecting mosaicism in ES.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a005231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304353PMC
June 2020

Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression.

Nat Commun 2020 05 1;11(1):2156. Epub 2020 May 1.

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11-dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15547-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195452PMC
May 2020

MYCN amplification and ATRX mutations are incompatible in neuroblastoma.

Nat Commun 2020 02 14;11(1):913. Epub 2020 Feb 14.

Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX-histone chaperone complex, and that induced by MYCN-mediated metabolic reprogramming, leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-14682-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021759PMC
February 2020

pVACtools: A Computational Toolkit to Identify and Visualize Cancer Neoantigens.

Cancer Immunol Res 2020 03 6;8(3):409-420. Epub 2020 Jan 6.

McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.

Identification of neoantigens is a critical step in predicting response to checkpoint blockade therapy and design of personalized cancer vaccines. This is a cross-disciplinary challenge, involving genomics, proteomics, immunology, and computational approaches. We have built a computational framework called pVACtools that, when paired with a well-established genomics pipeline, produces an end-to-end solution for neoantigen characterization. pVACtools supports identification of altered peptides from different mechanisms, including point mutations, in-frame and frameshift insertions and deletions, and gene fusions. Prediction of peptide:MHC binding is accomplished by supporting an ensemble of MHC Class I and II binding algorithms within a framework designed to facilitate the incorporation of additional algorithms. Prioritization of predicted peptides occurs by integrating diverse data, including mutant allele expression, peptide binding affinities, and determination whether a mutation is clonal or subclonal. Interactive visualization via a Web interface allows clinical users to efficiently generate, review, and interpret results, selecting candidate peptides for individual patient vaccine designs. Additional modules support design choices needed for competing vaccine delivery approaches. One such module optimizes peptide ordering to minimize junctional epitopes in DNA vector vaccines. Downstream analysis commands for synthetic long peptide vaccines are available to assess candidates for factors that influence peptide synthesis. All of the aforementioned steps are executed via a modular workflow consisting of tools for neoantigen prediction from somatic alterations (pVACseq and pVACfuse), prioritization, and selection using a graphical Web-based interface (pVACviz), and design of DNA vector-based vaccines (pVACvector) and synthetic long peptide vaccines. pVACtools is available at http://www.pvactools.org.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-19-0401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056579PMC
March 2020

Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response.

Authors:
Elaine R Mardis

Genome Med 2019 11 20;11(1):71. Epub 2019 Nov 20.

Institute for Genomic Medicine at Nationwide Children's Hospital, The Ohio State University College of Medicine, Children's Drive, Colombus, OH, 43205, USA.

The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clearly lies in the genomic alterations that are associated with cancer onset and progression, including those that contribute to genomic instability and the resulting creation of novel peptide sequences that may present as neoantigens. The immune reaction to these unique 'non-self' peptides is frequently suppressed by the tumor itself, but the use of checkpoint blockade therapies, personalized vaccines, or a combination of these treatments may elicit a tumor-specific immune response that results in cell death. Massively parallel sequencing, coupled with different computational analyses, provides unbiased identification of the germline and somatic alterations that drive cancer development, and of those alterations that lead to neoantigens. These range from simple point mutations that change single amino acids to complex alterations, such as frameshift insertion or deletion mutations, splice-site alterations that lead to exon skipping, structural alterations that lead to the formation of fusion proteins, and other forms of collateral damage caused by genome instability that result in new protein sequences unique to the cancer. The various genome instability phenotypes can be identified as alterations that impact DNA replication or mismatch repair pathways or by their genomic signatures. This review provides an overview of current knowledge regarding the fundamentals of genome replication and of both germline and somatic alterations that disrupt normal replication, leading to various forms of genomic instability in cancers, to the resulting generation of neoantigens and, ultimately, to immune-responsive and resistant phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-019-0684-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865009PMC
November 2019

Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens.

Proc Natl Acad Sci U S A 2019 11 4;116(47):23662-23670. Epub 2019 Nov 4.

Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer neoantigen vaccines. Here, we performed deep targeted DNA sequencing of multiple metastases from melanoma patients and observed ubiquitous sharing of clonal and subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted neoantigen epitopes. However, spontaneous antitumor CD8+ T cell immunity in peripheral blood and tumors was restricted to a few clonal neoantigens featuring an oligo-/monoclonal T cell-receptor (TCR) repertoire. Moreover, in various tumors of the 4 patients examined, no neoantigen-specific TCR clonotypes were identified despite clonal neoantigen expression. Mature dendritic cell (mDC) vaccination with tumor-encoded amino acid-substituted (AAS) peptides revealed diverse neoantigen-specific CD8+ T responses, each composed of multiple TCR clonotypes. Isolation of T cell clones by limiting dilution from tumor-infiltrating lymphocytes (TILs) permitted functional validation regarding neoantigen specificity. Gene transfer of TCRαβ heterodimers specific for clonal neoantigens confirmed correct TCR clonotype assignments based on high-throughput TCRBV CDR3 sequencing. Our findings implicate immunological ignorance of clonal neoantigens as the basis for ineffective T cell immunity to melanoma and support the concept that therapeutic vaccination, as an adjunct to checkpoint inhibitor treatment, is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1906026116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876217PMC
November 2019

Immunotherapeutic Challenges for Pediatric Cancers.

Mol Ther Oncolytics 2019 Dec 28;15:38-48. Epub 2019 Aug 28.

The Research Institute at Nationwide Children's Hospital, Center for Childhood Cancer and Blood Diseases, The Ohio State University College of Medicine, Columbus, OH, USA.

Solid tumors contain a mixture of malignant cells and non-malignant infiltrating cells that often create a chronic inflammatory and immunosuppressive microenvironment that restricts immunotherapeutic approaches. Although childhood and adult cancers share some similarities related to microenvironmental changes, pediatric cancers are unique, and adult cancer practices may not be wholly applicable to our pediatric patients. This review highlights the differences in tumorigenesis, viral infection, and immunologic response between children and adults that need to be considered when trying to apply experiences from experimental therapies in adult cancer patients to pediatric cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omto.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804520PMC
December 2019
-->