scholarly journals Genetic driver mutations introduced in identical cell‐of‐origin in murine glioblastoma reveal distinct immune landscapes but similar response to checkpoint blockade

Glia ◽  
2020 ◽  
Vol 68 (10) ◽  
pp. 2148-2166 ◽  
Author(s):  
Zhihong Chen ◽  
Cameron J. Herting ◽  
James L. Ross ◽  
Ben Gabanic ◽  
Montse Puigdelloses Vallcorba ◽  
...  
Keyword(s):  
Checkpoint Blockade ◽  
Driver Mutations ◽  
Similar Response ◽  
Cell Of Origin ◽  
Identical Cell

Somatic mutational profile of Merkel cell carcinoma treated with immune checkpoint blockade: Preliminary results from a planned multiplatform analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21064-e21064
Author(s):  
Evan Rosenbaum ◽  
Ciara Marie Kelly ◽  
Christopher Andrew Barker ◽  
Travis Adamson ◽  
Hannah Kiesler ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Blockade ◽  
Driver Mutations ◽  
Exome Capture ◽  
Merkel Cell ◽  
Mutation Burden

e21064 Background: Merkel cell carcinoma (MCC) is an immunogenic neuroendocrine malignancy with promising responses to immune checkpoint blockade (ICB). Although ICB is standard of care in advanced MCC patients, approximately 50% of patients are resistant to ICB. Thus, it is crucial to identify biomarkers predictive of response. Methods: To understand the genomic landscape of MCC, we performed exome capture sequencing on 27 tumor and matched normal samples from 25 patients with MCC treated at Memorial Sloan Kettering. Herein, we report the analysis of 16 paired samples from 14 patients. Nonsynonymous, high-confidence somatic mutations were identified and tumor reads aligned to the Merkel cell polyoma virus (MCPyV) were quantified. Results: Tumor and matched normal samples were sequenced to a median target coverage depth of 53x and 79x reads, respectively. One sample was not analyzed due to inadequate coverage. The MCPyV genome was detected in 12 of 13 patients (92%). The median somatic mutation burden among analyzed samples was 19 nonsynonymous variants per exome (range: 8 - 120). No recurrent driver mutations were identified in any sample. Four samples lacked potential driver mutations and, among the remaining 11 samples, 36 putatively oncogenic mutations were detected in 33 genes (variant allele frequency: 0.08 – 1), including genes involved in the cell cycle checkpoint ( TP53, RB1), DNA damage repair ( ERCC4, FANCA, FANCD2), PI3K-AKT-mTOR ( PIK3CA, PIK3CG), and Notch ( NOTCH1, NOTCH2) pathways. One sample with undetected MCPyV DNA demonstrated loss of heterozygosity of both TP53 and RB1. Four samples contained strand coordinated clusters of mutations in more than 20 distinct gene regions, suggesting an APOBEC-high mutagenesis signature. Conclusions: The MCPyV genome was detected in most tumors analyzed and tumor mutation burden was low in such tumors, consistent with published literature. Analysis of an additional 11 sample pairs is ongoing, along with personalized neoantigen binding predictions on all samples. Immunohistochemistry (IHC) for PDL1 and CD8 expression is in progress. Associations between the aforementioned and response to ICB will be reported.

scholarly journals Molecular and Cell Biological Considerations in the Initiation and Development of Sporadic Non-Hereditary Solid Cancers

2018 ◽  
pp. 24-40 ◽  
Author(s):  
Vladimir F. Niculescu
Keyword(s):  
Cancer Cell ◽  
Gene Networks ◽  
Complex Disease ◽  
Regulatory Gene ◽  
Life Cycles ◽  
Driver Mutations ◽  
Stable Gene ◽  
Cell Of Origin ◽  
Reproductive Process ◽  
Daughter Cells

This paper reviews the state of cancer research in the post-mutation era. It presents cancer as a highly complex disease viewed differently by scientists from various research fields. Histopathologists considered cancer as a disease of cell differentiation, cancer cell biologists overestimated the causal role of accumulated DNA mutations. More recently molecular biologists have focused on driver genes and driver mutations, regulatory gene networks and deregulation of the genomic balance between unicellular and multicellular gene sets (UG/MG balance). From a developmental biological standpoint, there is a clear analogy between the reproductive life cycles of cancer and protists. The key player of both analogous life cycles is the polyploid cyst, the atavistic cyst-like structure aCLS (PGCC). In the analogy to protists, we assume that the first aCLS initiating cancer originates from a mitoticly blocked cell (cell of origin of cancer, protoprecursor) that escapes death entering an atavistic reproductive process of polyploidisation and depolyploidisation; it forms the atavistic cyst-like structure aCLS and numerous daughter cells (microcells). The microcell progeny develops a multi-lined cell lineage containing stem cells as well as somatic and reproductive cells and clones. Subsequent aCLSs are formed sequentially by committed daughter cells or occasionally by stressed somatic cells. Accordingly, cancer initiation occurs by genomic changes leading to the amitotic cell state and reactivation of an atavistic life cycle. In humans, atavistic life cycles and hyperpolyploidisation (n >16) are mostly repressed by stable gene regulatory networks – but not in cancer. The permanent UG/MG gene conflict and robust ancient surveillance mechanisms trigger a cascade of molecular lesions leading to genomic heterogeneity and aberrant cancer cell states.

scholarly journals Genetic Architectures and Cell-of-Origin in Glioblastoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Hyun Jung Kim ◽  
Jung Won Park ◽  
Jeong Ho Lee
Keyword(s):  
Brain Cancer ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Fundamental Issue ◽  
Cell Of Origin ◽  
Cellular Origin ◽  
Common Cancer ◽  
The Central Nervous System ◽  
Glial Precursor ◽  
Novel Therapeutic

An aggressive primary brain cancer, glioblastoma (GBM) is the most common cancer of the central nervous system in adults. However, an inability to identify its cell-of-origin has been a fundamental issue hindering further understanding of the nature and pathogenesis of GBM, as well as the development of novel therapeutic targets. Researchers have hypothesized that GBM arises from an accumulation of somatic mutations in neural stem cells (NSCs) and glial precursor cells that confer selective growth advantages, resulting in uncontrolled proliferation. In this review, we outline genomic perspectives on IDH-wildtype and IDH-mutant GBMs pathogenesis and the cell-of-origin harboring GBM driver mutations proposed by various GBM animal models. Additionally, we discuss the distinct neurodevelopmental programs observed in either IDH-wildtype or IDH-mutant GBMs. Further research into the cellular origin and lineage hierarchy of GBM will help with understanding the evolution of GBMs and with developing effective targets for treating GBM cancer cells.

scholarly journals TBIO-09. IN SILICO ANALYSIS IDENTIFIES A PUTATIVE CELL-OF-ORIGIN FOR BRAF FUSION-POSITIVE CEREBELLAR PILOCYTIC ASTROCYTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii468-iii468
Author(s):  
Subhi Talal Younes
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Pilocytic Astrocytoma ◽  
Mapk Pathway ◽  
Ventricular Zone ◽  
In Silico Analysis ◽  
Developmental Trajectory ◽  
Driver Mutations ◽  
Cell Of Origin ◽  
Braf Fusion

Abstract Childhood cancers are increasingly recognized as disorders of cellular development. This study sought to identify the cellular and developmental origins of cerebellar pilocytic astrocytoma, the most common brain tumor of childhood. By leveraging publicly available gene expression data from such tumors and controlling for driver mutations, a set of eight known neuro-developmental genes were identified as being upregulated in cerebellar pilocytic astrocytoma. Mapping those genes onto mouse neuro-developmental atlases identified significant overlap in their expression within the ventricular zone of the cerebellar anlage. Further analysis with a single cell RNA-sequencing atlas of the developing mouse cerebellum defined this overlap as occurring in ventricular zone progenitor cells at the division point between GABA-ergic neuronal and glial lineages, a developmental trajectory which closely mirrors that previously described to occur within pilocytic astrocytoma cells. Furthermore, ventricular zone progenitor cells and their progeny exhibited evidence of MAPK pathway activation, the paradigmatic oncogenic cascade known to be active in cerebellar pilocytic astrocytoma. Gene expression from developing human brain atlases recapitulated the same anatomic localizations and developmental trajectories as those found in mice. Taken together, these data suggest this population of ventricular zone progenitor cells as the cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma.

scholarly journals A deep learning system can accurately classify primary and metastatic cancers based on patterns of passenger mutations

2017 ◽  
Author(s):  
Wei Jiao ◽  
Gurnit Atwal ◽  
Paz Polak ◽  
Rosa Karlic ◽  
Edwin Cuppen ◽  
...  
Keyword(s):  
Deep Learning ◽  
Learning System ◽  
Driver Mutations ◽  
Metastatic Tumour ◽  
Cancer Type ◽  
Cell Of Origin ◽  
Metastatic Recurrence ◽  
Learning Classifier ◽  
Previously Treated ◽  
Passenger Mutations

In cancer, the primary tumour's organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of the time a cancer patient presents with metastatic tumour and no obvious primary. Challenges also arise when distinguishing a metastatic recurrence of a previously treated cancer from the emergence of a new one. Here we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types. Our classifier achieves an accuracy of 91% on held-out tumor samples and 82% and 85% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced classifier accuracy. Our results have immediate clinical applicability, underscoring how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of cell-free circulating tumour DNA.

Do juxtaposed compound nevus and neurofibroma with melanocytic differentiation share an identical cell of origin in NF1?

2015 ◽  
Vol 25 (6) ◽  
pp. 615-617 ◽  
Author(s):  
Anja Harder ◽  
Mario Tippmar ◽  
Sergej Baschinskij ◽  
Christoph Rancso ◽  
Jan Janda ◽  
...  
Keyword(s):  
Cell Of Origin ◽  
Identical Cell ◽  
Melanocytic Differentiation

scholarly journals Whole-Exome Analysis Reveals Novel Somatic Genomic Alterations Associated with Cell of Origin in Diffuse Large B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2935-2935
Author(s):  
Kerstin Wenzl ◽  
Bryce Manso ◽  
Yan W Asmann ◽  
Matthew J Maurer ◽  
Michelle Manske ◽  
...  
Keyword(s):  
B Cell ◽  
Expression Profiling ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Driver Mutations ◽  
Cell Of Origin ◽  
Genomic Alterations ◽  
Large B Cell Lymphoma ◽  
Whole Exome

Abstract Gene expression profiling has shown that diffuse large B-cell lymphoma (DLBCL) clusters into three major subtypes based on similarity in expression patterns to their cell of origin (COO): germinal center B-cell-like (GCB-DLBCL), activated B-cell-like DLBCL (ABC-DBLCL) and primary mediastinal B-cell lymphoma (PMBCL). These subtypes of DLBCLs are associated with distinctly different overall survival rates after standard immunochemotherapy. However, clinical and prognostic heterogeneity remains within COO subsets and strategies are needed to further stratify patients to identify and target high-risk subsets. A comprehensive genomic analysis of COO on a clinically defined set of DLBCL cases has not been performed and the aim of this study was to use whole-exome sequencing (WES) data from 58 paired tumor-normal DLBCL samples to assess association of known DLBCL genomic alterations with cell COO as well as for identification of novel and relevant genetic biomarkers. To investigate genomic alterations associated with DLBCL subsets, we analyzed WES and genome wide copy number data from 58 paired tumor-normal DLBCL tumors. Gene expression profiling or Hans classification was performed to determine DLBCL COO subtype; 31 patients were classified as GCB and 27 as non-GCB. The WES data were used to 1) assess the association of known DLBCL genomic alterations with COO, and 2) identify novel alternations associated with COO. Statistical analysis was performed and the data were ranked by significance (p≤ 0.05) within each DLBCL subtype. In total, 45 genomic abnormalities were analyzed for their association with either GCB, non-GCB or both. Mutations in CREBBP, EZH2, MEF2B, FOXO1 and REL have also been reported as GCB driver mutations and we observed GCB patients with these mutations, but the mutation clustering was not wholly associated with GCB. MYC double-hits were exclusively found in the GCB-subtype group. For the non-GCB cases we found that mutations in MAP2K3 and MYD88 were significantly associated with this subtype(p< 0.05). In addition to mutational patterns, we identified several copy number alterations (CNA) across both groups. Chromosomal losses in GCB patients were found at chromosomes 10q11.21-10q24.23, 4q12-4q35.2, 3q12.1-3q29, 4p12-4p16.3, 10p11.21-10p15.3, and 14q11.2-14q24.3 whereas gains were localized to 7q11.1-7q36.3, 7p11.2-7p22.3, and 1q21-1q32.1 (p < 0.05). No CNA was observed to directly associate with non-GCB patients, however, a loss at 9p21 and gains at 9q24.1 and 18q21.33 trended with the non-GCB subtype, supporting previous reports. Loss at 10q23.31 or a gain in 2p13-2p12 have been reported as being specific for GCB and our data confirmed the association of 10q23.31 with GCB while a gain at 2p13-2p12 (REL)was found in both subtypes. To further understand genomic differences between DLBCL subtypes, we evaluated the relative percentage of each genomic feature. 18/45 (40%) were only observed in GCB patients whereas 2/45 (5%) were specific to the non-GCB subtype. The majority (25/45, 55%) overlapped between the two subtypes. Throughout our analysis we noted that 7 non-GCB cases lacked any of the driver mutations analyzed in the study. While all cases carried mutations, they consisted of low frequency mutations that were not specifically associated with COO. 2/7 cases had a gain at 9p24.1 that included CD274 and JAK2. Because 9p24.1 gains have not been fully defined in DLBCL, we reviewed all cases and identified 4 (7%) with a 9p24.1 gain, 3 of which were non-GCB and 1 GCB. One non-GCB case was EBV+ and none of the cases showed evidence of PMBCL. Of the 9p24.1 cases, three had RNAseq data available and we found that PDL1 and JAK2 expression was elevated (12 fold p< 0.01 and 7 fold p< 0.01, respectively) when compared to the 9p24.1 normal cases (n=32). While outcome was not the focus of the study, we did note that 6/7 cases that lacked driver mutations achieved event free survival at 24 months (EFS24). Taken together, this analysis has further characterized the genetic profile of each COO subtype and has identified novel GCB CNAs which require independent replication. Additionally, we identify a subgroup of non-GCB DLBCL patients that do not harbor known driver mutations and require further genomic study to better resolve the biology of these tumors. Together, these data provide insight on the genetic heterogeneity of DLBCL and identify genetic variants that may inform subtype specific therapy. Disclosures Nowakowski: Morphosys: Research Funding; Celgene: Research Funding; Bayer: Consultancy, Research Funding. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL..

Frequent Clinical Overlap of Histiocytic Neoplasms and WHO-Classified Myeloid Malignancies Leads to Functional Insights into the Cell-of-Origin of Histiocytoses

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 951-951 ◽  
Author(s):  
Benjamin Heath Durham ◽  
Akihide Yoshimi ◽  
Matthias Papo ◽  
Young Rock Chung ◽  
Neval Ozkaya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Flow Cytometric Analysis ◽  
Driver Mutations ◽  
Cell Of Origin ◽  
Hematopoietic Stem ◽  
Myeloid Malignancies ◽  
Hematological Disorders ◽  
Myeloid Neoplasm ◽  
Cd34 Cells

Abstract The identification of mutations in BRAFV600E and other kinases in systemic histiocytoses changed our understanding of the pathophysiology of these disorders from inflammatory non-malignant conditions to clonal disorders driven by altered MAP kinase signaling. In addition, BRAFV600E mutations have recently been noted in bone marrow (BM) CD34+ cells of patients with Langerhans Cell Histiocytosis (LCH), suggesting that LCH represents a clonal disorder arising from hematopoietic stem/progenitor cells (HSPCs). However, it is unknown if HSPCs from LCH or other histiocytoses patients can functionally give rise to these disorders. Moreover, whether or not patients with histiocytosis have additional hematological disorders related to the presence of HSPC-based mutations is unclear. Here we attempted to understand the spectrum of hematological disorders in patients with histiocytoses and the cell-of-origin of histiocytic neoplasms by functionally analyzing HSPCs from histiocytoses patients. We first analyzed a multicenter cohort of 190 adult histiocytoses patients. This unexpectedly identified a high frequency of patients with a co-existing myeloid malignancy. Of the 190 patients, 9.5% (18/190) were diagnosed with Erdheim-Chester Disease (ECD) and/or LCH concomitantly with a classic MPN (3.7%; 7/190), MPN/MDS overlap (4.7%; 9/190), or MDS (1.1%; 2/190) (Figure). This clinical observation was confirmed by detection of co-existing histiocytoses-associated kinase mutations (including BRAF, MAP2K1, NRAS, or KRAS mutations) with JAK2 or CALR mutations, as well as other mutations recurrently found in myeloid malignancies (such as IDH1/2, ASXL1, and TET2 mutations (Figure)). These data therefore reveal a heretofore-unrecognized clinical overlap of adult-onset systemic histiocytoses and WHO-classified myeloid malignancies while further highlighting the possibility of an aberrant HSPC origin for histiocytic neoplasms. In most cases, the BRAF/MAP2K1/RAS mutation predominated in the histiocytic lesion while the JAK2/CALR mutation predominated in the BM/peripheral blood suggesting likely distinct clones driving each clinical condition. Next, to test the self-renewal and differentiation capacity of HSPCs from histiocytoses patients, CD34+ cells were purified from 8 patients including 6 with ECD or LCH plus a concomitant myeloid neoplasm, and 2 with ECD alone. 0.1-0.8x106 CD34+ cells from each patient were transplanted by intrafemoral injection into sublethally irradiated NOD/SCID IL2Rγ transgenic human GM-CSF, IL-3, and SCF expressing (NSG-SGM3) mice. Human engraftment was monitored by monthly flow cytometric analysis of peripheral blood until mice became moribund. Thereafter, animals were sacrificed and tissues were analyzed using flow cytometry, histology, immunohistochemistry, and sequencing analyses to detect driver mutations identified in the histiocytosis/co-occurring myeloid neoplasm. Successful engraftment of human myeloid cells was verified in grafts generated from 2/8 patients after a mean of 90 days (range: 60-120 days). This included lethal engraftment of KRAS-mutated ECD patient cells at 90 days manifested by infiltration of human hCD45+ cells co-expressing human myeloid and monocyte lineage markers hCD33 and hCD14 in the bone marrow, spleen, liver, lung, and kidney (Figure). Immunostains revealed that tissues were infiltrated by an hCD45+hCD163+hCD68+ population of foamy histiocytes, characteristic of ECD (Figure). Furthermore, genomic analysis of DNA from the engrafted animals BM and spleen revealed the same KRASG12S mutation found in the donor patients ECD lesion. Engraftment of a patient diagnosed with concomitant BRAFV600E-mutant ECD and ASXL1/TET2-mutant CMML was seen at 60 days. In this case, however, only engraftment of human CMML was detected without evidence of the BRAFV600E-mutant ECD component. This study suggests that adult histiocytic neoplasms frequently co-occur with other myeloid neoplasms. Moreover, histiocytosis disease-driver mutations are present in the CD34+ HSPCs, which we show for the first time can initiate disease that resembles human histiocytosis in a patient-derived xenograft. Importantly, however, even though the CD34+ compartment gives rise to both the histiocytic and myeloid neoplasm disease component, each disease is likely initiated by distinct precursors. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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