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  • 1
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    Subclonal Somatic Copy-Number Alterations Emerge and Dominate in Recurrent Osteosarcoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research ( 2023-10-09), p. OF1-OF17
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), ( 2023-10-09), p. OF1-OF17
    Abstract: Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease. Significance: The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-23-0385
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors
    Springer Science and Business Media LLC ; 2021
    In:  Nature Cancer Vol. 2, No. 3 ( 2021-02-15), p. 357-365
    Details
    In: Nature Cancer, Springer Science and Business Media LLC, Vol. 2, No. 3 ( 2021-02-15), p. 357-365
    Type of Medium: Online Resource
    ISSN: 2662-1347
    URL: Article
    DOI: 10.1038/s43018-021-00172-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 3
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    Abstract B022: Subclonal somatic copy number alterations emerge and dominate in relapsed/refractory osteosarcoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 18_Supplement ( 2022-09-15), p. B022-B022
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 18_Supplement ( 2022-09-15), p. B022-B022
    Abstract: Objective: Multiple large-scale tumor genomic profiling efforts have been undertaken in osteosarcoma, however little is known about the spatial and temporal intratumor heterogeneity and how it may drive treatment resistance. Methods: We performed 30-80x whole genome sequencing (WGS) of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and one sample from a metastatic or relapse site. A set of high confidence single nucleotide variants (SNV), copy number alterations (CNA), structural variations (SV) were called for each sample using our pediatric expanded genomics pipeline and an evolutionary analysis was performed using a custom pipeline of computational tools. Results: Of the 8 patients in our cohort, 4 had localized disease at diagnosis (OSCE4, OSCE5, OSCE6, OSCE9) and 4 had metastatic disease at diagnosis (OSCE1, OSCE2, OSCE3, OSCE10). There were 17 samples from primary sites, 7 were pretreatment biopsies, 10 from on therapy primary resections. 20 samples came from metastatic sites, 15 of which were from lung metastases. Driver gene SNV’s were identified in 5 of 8 patients, including TP53 (OSCE1), ATRX (OSCE3, OSCE10), RB1 (OSCE4), and CDKN2A (OSCE9). There were no new driver SNV’s that emerged post-therapy in any patient. HATCHet, an algorithm that infers clone-specific copy number alterations, identified subclonal CNAs in all but one patient (OSCE2). In the 7 patients with subclonal CNAs, 6 had two copy number clones identified, and 1 patient (OSCE10) had three copy number clones identified. In 5 patients (OSCE1, OSCE4, OSCE5, OSCE6, OSCE10) there is a copy number clone that is subclonal in the primary tumor which emerges and dominates at subsequent relapses. The resistant clone in each of these cases had either MYC gain/amplification. Amplifications in CCNE1 (OSCE1), RAD21 (OSCE4, OSCE5, OSCE10), VEGFA (OSCE1, OSCE9), IGF1R (OSCE6) were also identified as potential drivers in the resistant copy number clones. In two of these patients (OSCE1, OSCE6), this treatment-resistant subclone becomes the dominant copy number clone by the time of primary resection. SNV based phylogenies revealed a heterogenous mix of monoclonal and polyclonal seeding of metastases and monophyletic and polyphyletic modes of dissemination. Over half the new mutations acquired in recurrent disease were attributed to HRD or cisplatin mutational signatures. TP53 structural variants were seen in 6/8 patients (OSCE2, OSCE3, OSCE4, OSCE6, OSCE9, OSCE10). New structural variants involving driver genes were only detected in one relapse sample from patient OSCE10 (DMD deletion). Conclusion: Subclonal copy number clones emerge and dominate in relapsed osteosarcoma, with MYC gain/amplification a defining characteristic in our cohort. Selective pressure from neoadjuvant chemotherapy reveals this clone at the time of primary resection, highlighting that genomic profiling at this time point may be more reflective of its metastatic potential. Citation Format: Michael D. Kinnaman, Simone Zaccaria, Alvin Makohon-Moore, Gunes Gundem, Juan E. Arango Ossa, Nancy Bouvier, Filemon S. Dela Cruz, Meera Hameed, Julia Lynne Glade Bender, William D. Tap, Paul Meyers, Elli Papaemmanuil, Andrew Kung, Christine A. Iacobuzio-Donahue. Subclonal somatic copy number alterations emerge and dominate in relapsed/refractory osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B022.
    Type of Medium: Online Resource
    ISSN: 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.SARCOMAS22-B022
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
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    ETV6-FLT3– positive myeloid/lymphoid neoplasm with eosinophilia presenting in an infant: an entity distinct from JMML
    American Society of Hematology ; 2021
    In:  Blood Advances Vol. 5, No. 7 ( 2021-04-13), p. 1899-1902
    Details
    In: Blood Advances, American Society of Hematology, Vol. 5, No. 7 ( 2021-04-13), p. 1899-1902
    Abstract: Myeloid/lymphoid neoplasm with eosinophilia (MLN-Eo) is a World Health Organization (WHO) established category of hematologic malignancies primarily arising in adults. We discuss an 8-month-old infant who presented with clinical features similar to those of juvenile myelomonocytic leukemia (JMML) but who was diagnosed with MLN-Eo driven by an ETV6-FLT3 fusion. Results of patient-derived leukemia ex vivo studies demonstrated increased sensitivity to type I FLT3 inhibitors as compared with type II inhibitors. Treatment with the type I inhibitor gilteritinib resulted in complete immunophenotypic and cytogenetic remission. This patient subsequently underwent a hematopoietic stem cell transplant and remains in complete remission 1 year later. This is the youngest patient reported with an ETV6-FLT3 fusion and adds to the mounting reports of FLT3-rearranged MLN-Eo, supporting its addition to the WHO classification. Furthermore, this case highlights the clinical utility of ex vivo drug testing of targeted therapies.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2020003699
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 5
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    Feasibility and clinical utility of cancer whole genome and transcriptome sequencing for pediatric and young adult solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 3063-3063
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3063-3063
    Abstract: 3063 Background: Next generation sequencing (NGS) assays have accelerated the identification of mutations and potential matched targeted therapies for patients with cancer. However, a significant proportion of patients do not derive clinical benefit from targeted panel sequencing approaches. Cancer whole genome and transcriptome sequencing (cWGTS) offers the opportunity to fully characterize tumors, but are challenged by significant cost and computational resource requirements, concerns of assay sensitivity, and the need to deliver curated results within clinically relevant time frames. We performed a prospective study to evaluate the feasibility and utility of cWGTS in pediatric and young adults with solid tumors. Methods: We developed an automated analytical workflow (Isabl) for the QC and processing of cWGTS data to include ensembl variant calling for germline and somatic substitutions, indels, and structural variants; fusion genes; gene expression; and mutation signatures. Treatment biomarkers were annotated using OncoKB with generation of a clinical prototype report. We tested the feasibility of cWGTS implementation, evaluated its analytical validity compared to standard diagnostic assays, and characterized the clinical utility of incremental findings in a prospective study of children and young adults treated at Memorial Sloan Kettering Cancer Center. Results: A total of 114 patients were enrolled. Standard NGS assays (MSK-IMPACT, MSK-Fusion) identified clinically relevant biomarkers in 22% of cases. The cWGTS process was completed, from sample acquisition to summary report, in less than 12 days. Comparison against clinically reported NGS results demonstrated high precision and recall for reported mutations (98.8%) with high concordance across variant allele representations (r 2 〉 0.73). cWGTS identified additional oncogenic mutations not captured by targeted sequencing in 49% of patients. Furthermore, incremental findings, beyond those identified by NGS assays, of direct clinical relevance (diagnostic, prognostic, therapy guiding) were identified in 26% of patients. Importantly, 〈 5% of the incremental findings would have been captured by whole exome or transcriptome sequencing alone. Of possible therapeutic relevance, cWGTS analyses revealed a significantly higher tumor mutation burden than previously reported (range: 0 - 11.23). Conclusions: We demonstrate feasibility, analytical validity and clinical utility of cWGTS approaches in pediatric and young adult cancer patients, with nearly half of all patients having incremental findings that were not captured by standard targeted NGS approaches.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.3063
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 6
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    Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 11533-11533
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 11533-11533
    Abstract: 11533 Background: Multiple large-scale tumor genomic profiling efforts have been undertaken in osteosarcoma, however little is known about the spatial and temporal intratumor heterogeneity and how it may drive treatment resistance. Methods: We performed 30-80x whole genome sequencing (WGS) of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. A set of high confidence single nucleotide variants (SNV), copy number alterations (CNA), structural variations (SV) were called for each sample using our pediatric expanded genomics pipeline and an evolutionary analysis was performed using a custom pipeline of computational tools. Results: Of the 8 patients in our cohort, 4 had localized disease at diagnosis (OSCE4, OSCE5, OSCE6, OSCE9) and 4 had metastatic disease at diagnosis (OSCE1, OSCE2, OSCE3, OSCE10). There were 17 samples from primary sites, 7 were pretreatment biopsies, 10 from on therapy primary resections. 20 samples came from metastatic sites, 15 of which were from lung metastases. Driver gene SNV’s were identified in 5 of 8 patients, including TP53 (OSCE1), ATRX (OSCE3, OSCE10), RB1 (OSCE4), and CDKN2A (OSCE9). No new driver SNV’s emerged post-therapy in any patient. HATCHet, an algorithm which infers clone specific copy number alterations, identified subclonal CNAs in all but one patient (OSCE2). In the 7 patients with subclonal CNAs, 6 had two copy number clones identified, and 1 patient (OSCE10) had three copy number clones identified. In 5 patients (OSCE1, OSCE4, OSCE5, OSCE6, OSCE10) there is a copy number clone that is subclonal in the primary tumor which emerges and dominates at subsequent relapses. The resistant clone in each of these cases had either MYC gain/amplification. Amplifications in CCNE1 (OSCE1), RAD21 (OSCE4, OSCE5, OSCE10), VEGFA (OSCE1, OSCE9), IGF1R (OSCE6) were also identified as potential drivers in the resistant copy number clones. In two of these patients (OSCE1, OSCE6), the treatment resistant subclone becomes the dominant copy number clone by the time of primary resection. SNV based phylogenies revealed monoclonal and polyclonal seeding of metastases and monophyletic and polyphyletic modes of dissemination. Over half the new mutations acquired in recurrent disease were attributed to HRD or cisplatin mutational signatures. Conclusions: Subclonal copy number clones emerge and dominate in relapsed osteosarcoma, with MYC gain/amplification a defining characteristic in our cohort. Selective pressure from neoadjuvant chemotherapy reveals this clone at the time of primary resection, implying genomic profiling at this timepoint may be more reflective of its metastatic potential. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.11533
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 7
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    Abstract 704: Development of a patient-derived xenograft (PDX) modeling program to enable pediatric precision medicine
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 704-704
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 704-704
    Abstract: Background: Recapitulation of the full spectrum of genomic changes driving patient tumors have resulted in increased use of patient-derived xenograft (PDX) models in studies of basic cancer biology and preclinical drug development. Given the translational potential of PDXs and limited availability of pediatric cancer models, we established a PDX program to expand the existing collection of pediatric PDXs in the community and enable pre- and post-clinical studies. Methods: PDX generation requests were integrated into clinical workflows to maximize identification of eligible patients for informed consent and tissue collection at Memorial Sloan Kettering Cancer Center. Methodologies for tissue procurement and cryopreservation were optimized to facilitate implantation into host immunodeficient mice and enable multi-institutional tissue exchange for model building. A bioinformatics pipeline was established to allow molecular validation of engrafted PDXs using a next-generation targeted gene panel (MSK-IMPACT) evaluating concordance based on acquired mutations, copy number alterations and clonal structure. Results: Between November 2016 - October 2021, 379 PDX models were developed (265 distinct models) representing 69 discrete diagnoses. Sarcoma represents the most common model type (50 discrete osteosarcoma, 20 desmoplastic small round cell tumor, 14 Ewing sarcoma, 24 rhabdomyosarcoma, 2 CIC/DUX4 and 2 BCOR-rearranged sarcoma) followed by neuroblastoma (n=35), leukemia (n=44), and Wilms tumor (n=15). While the majority of PDXs were established from recurrent or metastatic tissue, 7 paired diagnostic/pre-therapy and post-therapy or relapse models were generated. Genomic characterization of PDXs demonstrate excellent concordance and recapitulation of single nucleotide variants (90%), structural (88%) and copy number variants (94%) between patient tumor and matched PDX. Discrepancies between matched patient/PDX pairs are due to sub-clonal heterogeneity in source tumors with clonal outgrowth in the PDX. Analysis of serial PDX passages also demonstrate stable recapitulation of the genomic profile. Establishment of a diverse PDX collection allowed preclinical evaluation of 10 targeted agents across a spectrum of pediatric tumors and provided the preclinical rationale for 3 investigator-initiated pediatric clinical trials. Conclusions: Investment in the development of a phenotypically diverse and biologically faithful collection of pediatric PDX models enables the goals of precision medicine. Optimization of PDX workflows and methods has also enabled the development of a pediatric PDX consortium (PROXC - Pediatric Research in Oncology Xenografting Consortium) to further support the development of pre- and post-clinical studies for pediatric cancer. Citation Format: Filemon S. Dela Cruz, Joseph G. McCarter, Daoqi You, Nancy Bouvier, Xinyi Wang, Kristina C. Guillan, Armaan H. Siddiquee, Katie B. Souto, Hongyan Li, Teng Gao, Dominik Glodzik, Daniel Diolaiti, Neerav N. Shukla, Joachim Silber, Umeshkumar K. Bhanot, Faruk Erdem Kombak, Diego F. Coutinho, Shanita Li, Juan E. Arango Ossa, Juan S. Medina-Martinez, Michael V. Ortiz, Emily K. Slotkin, Michael D. Kinnaman, Sameer F. Sait, Tara J. O'Donohue, Marissa Mattar, Maximiliano Meneses, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Nicola Fabbri, Chelsey M. Burke, Irene M. Rodriquez-Sanchez, Christine A. Iacobuzio-Donahue, Julia L. Glade Bender, Ryan D. Roberts, Jason T. Yustein, Nino C. Rainusso, Brian D. Crompton, Elizabeth Stewart, Alejandro Sweet-Cordero, Leanne C. Sayles, Andrika D. Thomas, Michael H. Roehrl, Elisa de Stanchina, Elli Papaemmanuil, Andrew L. Kung. Development of a patient-derived xenograft (PDX) modeling program to enable pediatric precision medicine [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 704.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-704
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
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    A recurrent novel MGA–NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma
    Cold Spring Harbor Laboratory ; 2018
    In:  Molecular Case Studies Vol. 4, No. 6 ( 2018-12), p. a003194-
    Details
    In: Molecular Case Studies, Cold Spring Harbor Laboratory, Vol. 4, No. 6 ( 2018-12), p. a003194-
    Abstract: NUTM1 -rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. NUTM1 -rearranged tumors display histologic features of a poorly differentiated carcinoma with areas of focal squamous differentiation and typically express the BRD4–NUTM1 fusion gene defining a distinct clinicopathologic entity—NUT carcinoma (NC). NCs with mesenchymal differentiation have rarely been described in the literature. In this report, we describe the characterization of two cases of high-grade spindle cell sarcoma harboring a novel MGA–NUTM1 fusion. Whole-genome sequencing identified the presence of complex rearrangements resulting in a MGA–NUTM1 fusion gene in the absence of other significant somatic mutations. Genetic rearrangement was confirmed by fluorescence in situ hybridization, and expression of the fusion gene product was confirmed by transcriptomic analysis. The fusion protein was predicted to retain nearly the entire protein sequence of both MGA (exons 1–22) and NUTM1 (exons 3–8). Histopathologically, both cases were high-grade spindle cell sarcomas without specific differentiation markers. In contrast to typical cases of NC, these cases were successfully treated with aggressive local control measures (surgery and radiation) and both patients remain alive without disease. These cases describe a new subtype of NUTM1 -rearranged tumors warranting expansion of diagnostic testing to evaluate for the presence of MGA–NUTM1 or alternative NUTM1 gene fusions in the diagnostic workup of high-grade spindle cell sarcomas or small round blue cell tumors of ambiguous lineage.
    Type of Medium: Online Resource
    ISSN: 2373-2865 , 2373-2873
    URL: Article
    DOI: 10.1101/mcs.a003194
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2018
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