scholarly journals Genomic Landscape of Intramedullary Spinal Cord Tumors Suggests Distinct Genetic Origins Compared to Intracranial Histopathologic Counterparts

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Tej D Azad ◽  
Ming Zhang ◽  
Rajiv Iyer ◽  
Qing Wang ◽  
Tomas Garzon-Muvdi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Treatment Options ◽  
Driver Mutations ◽  
Whole Genome ◽  
Spinal Cord Tumors ◽  
Intramedullary Spinal Cord ◽  
Molecular Features ◽  
The Central Nervous System

Abstract INTRODUCTION Intramedullary spinal cord tumors (IMSCTs) are a rare, heterogeneous group of neoplasms with limited treatment options and high rates of morbidity and mortality. Next-generation sequencing has revealed opportunities for targeted therapies of the intracranial counterparts of IMSCT, but little is known about the molecular features of IMSCT. METHODS To better understand the genetic basis of these tumors we performed whole exome sequencing on fifty-one IMSCT and matched germline DNA, including 29 ependymomas, 16 astrocytomas, 4 gangliogliomas,1hemangioblastoma, and 1 oligodendroglioma. Whole-genome sequencing was further performed on 12 IMSCT to discover possible structural variants. RESULTS Though recurrent somatic mutations in IMSCTs were rare, we identified NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identified copy number amplifications in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts did not harbor the canonical mutations associated with their intracranial counterparts (eg glioblastoma). CONCLUSION Our findings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides a framework to begin more biologically based therapeutic strategies.

scholarly journals Genomic Landscape of Intramedullary Spinal Cord Gliomas

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ming Zhang ◽  
Rajiv R. Iyer ◽  
Tej D. Azad ◽  
Qing Wang ◽  
Tomas Garzon-Muvdi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Genetic Basis ◽  
Somatic Mutations ◽  
Treatment Options ◽  
Driver Mutations ◽  
Spinal Cord Tumors ◽  
Intramedullary Spinal Cord ◽  
Whole Exome ◽  
Genomic Landscape ◽  
The Central Nervous System

AbstractIntramedullary spinal cord tumors (IMSCTs) are rare neoplasms that have limited treatment options and are associated with high rates of morbidity and mortality. To better understand the genetic basis of these tumors we performed whole exome sequencing on 45 tumors and matched germline DNA, including twenty-nine spinal cord ependymomas and sixteen astrocytomas. Though recurrent somatic mutations in IMSCTs were rare, we identified NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identified copy number amplifications in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts (e.g. glioblastoma) did not harbor the canonical mutations associated with their intracranial counterparts. Our findings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides the framework to begin more biologically based therapeutic strategies.

Nonenhancing tumors of the spinal cord

2007 ◽  
Vol 7 (4) ◽  
pp. 403-407 ◽  
Author(s):  
J. Bradley White ◽  
Gary M. Miller ◽  
Kennith F. Layton ◽  
William E. Krauss
Keyword(s):  
Spinal Cord ◽  
Common Finding ◽  
Subtotal Resection ◽  
Low Grade ◽  
Spinal Cord Tumors ◽  
Intramedullary Tumors ◽  
Intramedullary Spinal Cord ◽  
Tumor Invasiveness ◽  
The Central Nervous System ◽  
Tumor Types

Object Enhancement of pathological entities in the central nervous system is a common finding when the blood–brain barrier has been compromised. In the brain, the presence or absence of gadolinium enhancement is often an indicator of tumor invasiveness and/or grade. In the spinal cord, however, contrast enhancement has been shown in all tumor types, regardless of grade. In this study the authors explore the incidence of nonenhancing tumors of the spinal cord and the clinical course of patients with these lesions. Methods A retrospective analysis was conducted in which investigators examined the patterns of enhancement of histologically proven intramedullary spinal cord tumors that had been evaluated at the Mayo Clinic between 1998 and 2002. The tumors that did not enhance were the subject of this report. Results A total of 130 patients with intramedullary tumors were evaluated. Of those, 11 patients (9%) had tumors that did not enhance. Histologically, a majority of tumors were astrocytomas (eight low-grade and two high-grade lesions); one tumor was a subependymoma. Morphologically, most of the tumors were diffuse and none had associated cysts. Tumors spanned from two to seven levels and were located throughout the spinal cord (four cervical, three cervicothoracic, one thoracic, and three thoracolumbar). Biopsy procedures were performed in eight patients, subtotal resection was performed in two, and gross-total resection in one. After a mean follow-up period of 19 months, tumors remained stable in eight patients but progressed in three, two of whom died. Conclusions A number of intramedullary spinal cord tumors will not enhance after addition of contrast agents. The absence of enhancement does not imply the absence of tumor.

scholarly journals Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
J. -B. Cazier ◽  
◽  
S. R. Rao ◽  
C. M. McLean ◽  
A. K. Walker ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Somatic Mutations ◽  
Early Stage ◽  
Clonal Diversity ◽  
Driver Mutations ◽  
Low Grade ◽  
Alternative Mechanism ◽  
Whole Genome ◽  
Mutation Burden

Abstract Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former are not mutually exclusive with TP53 mutations or MDM2 amplification, showing that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade and greater clonal diversity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater diversity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression.

scholarly journals Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 754
Author(s):  
Helen R. Davies ◽  
Kevin D. Broad ◽  
Zerrin Onadim ◽  
Elizabeth A. Price ◽  
Xueqing Zou ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Driver Mutations ◽  
Whole Genome ◽  
Rb1 Gene ◽  
Clinical Screening ◽  
Genetic Changes ◽  
Alternative Pathways ◽  
Mutational Signature ◽  
New Mutations

The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks.

scholarly journals Comprehensive Mutational Analysis of Juvenile Myelomonocytic Leukemia Using Whole-Genome Sequencing

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2974-2974
Author(s):  
Yusuke Okuno ◽  
Hideki Muramatsu ◽  
Norihiro Murakami ◽  
Nozomu Kawashima ◽  
Manabu Wakamatsu ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Rna Sequencing ◽  
Genome Sequencing ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Driver Mutations ◽  
Juvenile Myelomonocytic Leukemia ◽  
Whole Genome ◽  
Ras Pathway ◽  
Myelomonocytic Leukemia

Background Juvenile myelomonocytic leukemia (JMML) is a rare and exclusively pediatric myelodysplastic/myeloproliferative neoplasm. This disease is genetically characterized by an extremely small number of somatic mutations (an average of 0.8 mutations/exome/patient). It has been shown that causative somatic and/or germline mutations activating the RAS pathway are located in PTPN11, NF1, NRAS, KRAS, and CBL in 85% of patients with JMML. Furthermore, up to 20% of the patients have additional secondary mutations including SETBP1, and JAK3 mutations. In 2% of the patients, we identified, by RNA sequencing, activating kinase lesions affecting ALK or ROS1. Such findings suggest that other kinase fusions are present in JMML. There is an exceptional scarcity of somatic passenger mutations on the exome, suggesting that a small number of driver mutations drive JMML. However, to date, this hypothesis has not been investigated by whole-genome sequencing. Patients and Methods We performed a whole-genome sequencing (WGS) study in 48 patients with JMML. Bone marrow specimens and in vitro-cultured T cells were used as tumor and germline samples, respectively. Next-generation sequencing was performed using a HiSeq X platform (Illumina). Data analysis was performed by our in-house pipeline. Specifically, the pipeline detects single nucleotide variants (SNVs), copy number variants, somatic loss of heterozygosity (LOH), and chromosomal structural variations (SVs). The study was approved by the institutional review board of Nagoya University Graduate School of Medicine. Results In each patient we detected an average of 28 somatic mutations. These were primarily C-to-T transition in the CpG context, indicating that the mutations occurred by cell division. Besides RAS pathway and known secondary mutations, we observed no significant accumulation of somatic mutations in either coding or non-coding regions. Although we detected RAS pathway mutations in 90% of the patients, all mutations were on exome. However, we identified germline microdeletions affecting CBL and NF1, which had not been identified by exome sequencing. Additionally, we found two LOH events that affected NF1. Bi-allelic inactivation of NF1 is generally observed in patients with JMML; however, no pathogenic SNVs were identified in these two patients. We identified two chromosomal translocations that caused activating kinase lesions (i.e., RANBP2-ALK and TBL1XR1-ROS1). These had been pointed out in our previous RNA sequencing study. Another patient carried a complex SV that affected XPO1 (encoding exportin 1 or chromosome region maintenance 1 protein homolog). Although fusion genes involving XPO1 are reported to be present in lymphoid malignancies, the role of this SV in JMML remains unclear. Conclusions JMML is characterized by driver mutations that are largely present within the exome. However, WGS can still play a role in identifying both coding and non-coding mutations. LOH events without pathogenic SNVs suggest the presence of novel regulatory mechanisms of NF1. Conclusively, JMML is characterized by a paucity of somatic alterations and driver mutations. Hence, current research efforts should focus on RAS pathway mutations and known secondary mutations, many of which can be targeted. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evaluation of the Molecular Pathogenesis of Adrenocortical Tumors by Whole-Genome Sequencing

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A68-A68
Author(s):  
Kerstin Neininger ◽  
Patrick May ◽  
Barbara Altieri ◽  
Juliane L Lippert ◽  
Kirsten Roomp ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Whole Genome ◽  
Cortisol Secretion ◽  
Structural Variations ◽  
Driver Genes ◽  
Pathogenic Variants ◽  
Autonomous Cortisol Secretion

Abstract Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. Our aim was to identify novel genetic alterations in adrenocortical adenomas (ACA) without somatic mutations in known driver genes. Whole-genome sequencing was performed on 26 ACA/blood-derived DNA pairs without driver mutations in PRKACA, GNAS and CTNNB1 genes at previous WES (ENSAT study JCEM 2016). These included 12 cortisol-producing adenomas with Cushing syndrome (CS-CPAs), 7 with mild autonomous cortisol secretion (MACS-CPAs), and 7 endocrine-inactive ACAs (EIAs). Seven adrenocortical carcinomas (ACC) were added to the cohort. We developed a bioinformatics pipeline for a comprehensive genome analysis and to reveal differences in variant distribution. Strelka, VarScan2 and ANNOVAR software and an in-house confidence score were used for variant calling and functional annotation. Combined Annotation-Dependent-Depletion (CADD) values were used to prioritize pathogenic variants. Additional focus relied on variants in pathogenically known pathways (Wnt/β-catenin, cAMP/PKA pathway). NovoBreak algorithm was applied to discover structural variations. Two hypermutated CS-CPA samples were excluded from further analysis. Using different filters, we detected variants in driver genes not observed at WES (one p.S45P in CTNNB1 and one p.R206L in PRKACA in two different CS-CPAs). In total, we report 179,830 variations (179,598 SNVs; 232 indels) throughout all samples, being more abundant in ACC (88,954) compared to ACA (CS-CPAs: 31,821; MACS-CPAs: 35,008; EIAs: 29,963). Most alterations were in intergenic (>50%), followed by intronic and ncRNA intronic regions. A total of 32 predicted pathogenic variants were found in both coding (CADD values ≥ 15) and non-coding (CADD values ≥ 5) regions. We found 3,301 possibly damaging and recurrent variants (intergenic mutations removed) (CS-CPAs: 1,463; MACS-CPAs: 1,549; EIAs: 1,268; ACC: 1,660), mostly accumulated in intronic regions. Some of these were detected in members of the Wnt/β-catenin (CS-CPAs: 6; MACS-CPAs: 2; EIA: 1) and cAMP/PKA (CS-CPAs: 6; MACS-CPAs: 7; EIA: 4) pathways (e.g. ADCY1, ADCY2, GNA13, PDE11A). We also found a slightly higher number of structural variations in EIA (3,620) and ACC (3,486) compared to CS-CPAs (977) and MACS-CPAs (2,119). In conclusion, still unrevealed genetic alterations, especially in intronic regions, may accompany early adrenal tumorigenesis and/or autonomous cortisol secretion.

scholarly journals A Prospective Analysis of the Genomic Landscape of Patients with Acute Myeloid Leukemia and Its Impact on Clinical Outcomes - Data from a Tertiary Care Center in India

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5163-5163
Author(s):  
Hamza Yusuf Dalal ◽  
Sharat Damodar ◽  
Vidya Harini Veldore ◽  
Coral Miriam K ◽  
Shilpa Prabhu ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Whole Genome Sequencing ◽  
Clinical Outcomes ◽  
Genome Sequencing ◽  
Myeloid Leukemia ◽  
Driver Mutations ◽  
Whole Genome ◽  
Intermediate Risk ◽  
Genomic Landscape ◽  
Acute Myeloid

BACKGROUND : Clinical Phenotype and outcomes of patients with Acute myeloid leukemia (AML) in the Indian subcontinent differs from published literature. A younger age at diagnosis and higher induction mortality complicate AML management in India(1). Metaphase Karyotyping represents the backbone of prognostication and risk stratification in AML. Optimal treatment strategies for the cohort of Cytogenetically normal AML are still under evaluation. Applications of Next generation Sequencing (NGS) techniques in AML have unravelled the genetic heterogeneity of this disease. Whole genome sequencing has identified many novel mutations leading to tremendous improvements in diagnosis and risk stratification. Development of therapies targeting these genetic alterations is enabling a gradual shift from non-specific approaches to personalised therapy tailored to an individual patient's genome. This will undoubtedly translate to better clinical outcomes for this disease, with otherwise poor prognosis. Whole genome sequencing is still in a nascent stage in Indian settings with no published literature on genomics in AML till date. We aimed to study the genomic landscape of AML in the Indian population and to co-relate this with clinical outcomes over the course of 1 year. METHODS: We recruited 34 newly diagnosed patients with AML who presented to our Centre (Mazumdar Shaw Medical Centre, Narayana Health City, Bangalore, India) between November 2017 and May 2018. Clinical and laboratory details of all patients were recorded. Bone marrow and paired peripheral blood samples were drawn before initiating therapy. Whole genome sequencing and Exome capture was done for each sample using Ilumina HiSeq platform. Patients were risk stratified as per ELN 2017 and treated as per NCCN guidelines. Patients were followed up prospectively for one year from initial diagnosis. Genetic results were stratified according to gene function and analysed with respect to predefined clinical outcomes (remission status post induction, relapse rates, progression free and overall survival). RESULTS: Amongst the 34 study participants, 5 patients failed QC during sequencing and were de-recruited. Hence 29 patients were available for final analysis. Median age of patients was 42 years with 13 patients (44.8%) less than 40 years of age.18 patients (60%) had normal cytogenetics at baseline.17 patients (58%) were classified as intermediate risk and 6 patients each as Standard and high risk, as per ELN 2017. 22 patients (79.3%) patients received standard Induction chemotherapy (3+7 regimen) while 6 patients received hypomethylating agents. Overall CR rate following induction at Day 28 was 50% and Induction mortality was 21.42%. 6 patients underwent an Allogenic Stem cell transplant. A total of 96 mutations (47 driver and 49 VUS mutations) in 123 genes were identified. The average number of Driver mutations was 1.48 per patient. IDH genes were the most frequently mutated Driver genes followed by FLT3 mutations. Frequency of NPM1 mutations was significantly low (17.25%). Highest frequency of VUS mutations was seen in the ETV6, ATM and CBLC genes. Highest frequency of somatic mutations were identified in the genes encoding for myeloid transcription factors and DNA methylation. Average driver mutations showed significant co-relation to Age (> 60 years) and high burden of Bone marrow blasts (>30%). An updated risk stratification incorporating mutation analysis findings resulted in re-stratification of 8 intermediate risk patients into high risk. 2 patients with detectable FLT3 ITD mutation by NGS were negative by PCR. Choice of consolidation therapy and Driver mutation status were found to show statistically significant association with both Event free survival and Overall survival at 1 year. Increased driver mutation burden was associated with increased refractoriness to chemotherapy and poor EFS and OS. Mutations in Tumour suppressor genes, were associated with suboptimal treatment outcomes and poor survival. CONCLUSIONS Genomic landscape of AML in Indian patients shows significant differences from published literature. This may hold clues to the differing biological characteristics of AML seen in this population. Genome based risk stratification and tailored therapy needs to be adapted into the management of AML. This data provides valuable insights into developing therapeutic strategies for Indian patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Intramedullary spinal cord tumors: a review of current and future treatment strategies

2015 ◽  
Vol 39 (2) ◽  
pp. E14 ◽  
Author(s):  
Matthew K. Tobin ◽  
Joseph R. Geraghty ◽  
Herbert H. Engelhard ◽  
Andreas A. Linninger ◽  
Ankit I. Mehta
Keyword(s):  
Spinal Cord ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Incidence Rates ◽  
Subtotal Resection ◽  
Spinal Cord Tumors ◽  
Intramedullary Spinal Cord ◽  
Low Incidence ◽  
New Research ◽  
Localized Drug Delivery

Intramedullary spinal cord tumors have low incidence rates but are associated with difficult treatment options. The majority of patients with these tumors can be initially treated with an attempted resection. Unfortunately, those patients who cannot undergo gross-total resection or have subtotal resection are left with few treatment options, such as radiotherapy and chemotherapy. These adjuvant treatments, however, are associated with the potential for significant adverse side effects and still leave patients with a poor prognosis. To successfully manage these patients and improve both their quality of life and prognosis, novel treatment options must be developed to supplement subtotal resection. New research is underway investigating alternative therapeutic approaches for these patients, including directed, localized drug delivery and nanomedicine techniques. These and other future investigations will hopefully lead to promising new therapies for these devastating diseases.

scholarly journals Decoding human cancer with whole genome sequencing: a review of PCAWG Project studies published in February 2020

2021 ◽  
Author(s):  
Simona Giunta
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Genetics ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Causative Mutation ◽  
Whole Genome ◽  
Genetic Changes ◽  
Pan Cancer

AbstractCancer is underlined by genetic changes. In an unprecedented international effort, the Pan-Cancer Analysis of Whole Genomes (PCAWG) of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) sequenced the tumors of over two thousand five hundred patients across 38 different cancer types, as well as the corresponding healthy tissue, with the aim of identifying genome-wide mutations exclusively found in cancer and uncovering new genetic changes that drive tumor formation. What set this project apart from earlier efforts is the use of whole genome sequencing (WGS) that enabled to explore alterations beyond the coding DNA, into cancer’s non-coding genome. WGS of the entire cohort allowed to tease apart driving mutations that initiate and support carcinogenesis from passenger mutations that do not play an overt role in the disease. At least one causative mutation was found in 95% of all cancers, with many tumors showing an average of 5 driver mutations. The PCAWG Project also assessed the transcriptional output altered in cancer and rebuilt the evolutionary history of each tumor showing that initial driver mutations can occur years if not decades prior to a diagnosis. Here, I provide a concise review of the Pan-Cancer Project papers published on February 2020, along with key computational tools and the digital framework generated as part of the project. This represents an historic effort by hundreds of international collaborators, which provides a comprehensive understanding of cancer genetics, with publicly available data and resources representing a treasure trove of information to advance cancer research for years to come.

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