BACKGROUNDNeuroblastoma is a common solid tumor of childhood and is often associated with hypertension. Potential etiologies contributing to hypertension include renal compression, pain, volume ...overload, and catecholamine secretion. CASESWe completed a single center retrospective review of children with neuroblastoma and ≥stage II hypertension (per Hypertension Canada guidelines) over a 2-year period. All patients (n = 10) had elevated urine normetanephrine levels and eight had intra-abdominal tumors. Four patients had refractory hypertension requiring > three agents, of which three required alpha/beta blockade. CONCLUSIONAlthough multifactorial, hypertension in neuroblastoma often has a neuroendocrine component. Excess normetanephrine production in neuroblastoma may be a more common hypertensive mechanism than previously appreciated. Urinary normetanephrine elevation could suggest potential neuroendocrine-mediated hypertension.
This is the first report of a NACC2‐NTRK2 fusion in a histological glioblastoma. Oncogenomic analysis revealed this actionable fusion oncogene in a pediatric cerebellar glioblastoma, which would not ...have been identified through routine diagnostics, demonstrating the value of clinical genome profiling in cancer care.
This is the first report of a NACC2‐NTRK2 fusion in a histological glioblastoma. Oncogenomic analysis revealed this actionable fusion oncogene in a pediatric cerebellar glioblastoma, which would not have been identified through routine diagnostics, demonstrating the value of clinical genome profiling in cancer care.
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Background: Metastatic sarcomas represent a heterogeneous, difficult to treat family of cancers with poor median overall survival of 18 months. While global sequencing initiatives ...have catalogued genomic variation among primary sarcomas, metastatic sarcoma is less well understood. Genome-guided targeted therapy has made promising advances but is difficult to study in sarcomas due to heterogeneity and low prevalence. Whole genome and transcriptome analysis (WGTA) can help elucidate sarcoma oncogenesis, metastasis, and potential therapeutic targets. Methods: Using whole genome (80X) and transcriptome (200M read) sequencing of 43 metastatic sarcomas across 19 subtypes, we analyzed structural variants (SV), copy-number variants (CNV), mutation signatures, gene expression, and the immune microenvironment. All prior treatments were retrieved through chart review. Results: 17 patients (40%) attempted WGTA-informed therapy, of which 8 (47%) were classified as responders. Metastatic sarcomas demonstrated recurrent CNVs, with 17p11-p12 amplification in 42% of cases. Some recurrent expression outliers were associated with potential targets (e.g. MYOCD, PMP22, COPS3) while others (e.g. ADORA2B) have not been previously observed in sarcoma. Discovery of oncogenic fusions refined diagnoses in two cases with atypical histology. Clustering by mutation signatures distinguished histological subtypes, and two signatures were novel in sarcoma: (1) a strong base excision repair signature associated with NTHL1 loss and (2) a cisplatin-associated signature exclusive to platinum-treated cases. Frequent homologous recombination deficiency was observed and was associated with response to ifosfamide in three leiomyosarcomas. Of four immunotherapy-treated cases, the only responder demonstrated outlier CIBERSORT immune infiltration score, which did not correlate with PD-L1 expression. Conclusions: This is the first in-depth WGTA of metastatic sarcoma. We found recurrent and potentially targetable CNVs, expression outliers, mutation signatures, and immune markers. Our results suggest that clinical translation is promising using actionable insights obtained through WGTA.
Abstract
Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized ...treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign, or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer-related information as part of the consent process for participation in the POG program. A subcommittee comprising medical geneticists, bioinformaticians, pathologists, oncologists, and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012-January 2017, 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, and 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high-penetrance mutations were already known to HCP. All VUS were reviewed by the subcommittee, taking into consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data were generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research-generated clinically relevant germline results to affected subjects.
Citation Format: Howard J. Lim, Kasmintan A. Schrader, Sean Young, Jessica M T Nelson, Alexandra Fok, Erin Pleasance, Martin Jones, Yaoqing Shen, Linlea Armstrong, Alice Virani, Shahrad Rassekh, Rebecca Deyell, Stephen Yip, Robyn Roscoe, Aly Karsan, Marco Marra, Janessa J. Laskin. Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A190.
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Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide ...personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.
Abstract
Aim: To investigate feasibility and utility of whole genome and RNA sequencing in cancer care. The use of comprehensive personal genomic information to guide cancer treatment decisions has ...gained momentum in recent years. Here we present the Personalized Oncogenomics (POG) project launched at British Columbia Cancer Agency in 2012. This project uses paired tumor/normal whole genome and transcriptome sequencing to characterize a patient's tumor and inform treatment options within a clinically relevant time frame. In the past 5 years, around 600 patients with metastatic cancers (including 49 pediatric cases) have been sequenced and analyzed, representing over 50 cancer types. The breadth and depth of data in POG enable the detection of multiple types of alterations, from simple mutations, indels, and copy number changes, to more complex alterations such as gene fusion, mutation signatures, and homologous recombination deficiency score. Incorporation of gene expression data through transcriptome sequencing informs on the impact of observed genomic alterations, and provides information regarding specific diagnosis via expression comparison to other cancer subtypes. All genomic and transcriptomic variants are integrated to build a personalized tumor-specific molecular profile, identify actionable items supported by an in-house knowledgebase and publically available molecular oncology, and characterize each individual tumor by intensive pathway analysis and literature search. Such multidimensional data also impose challenges in interpretation and communication. We developed a pipeline to translate complex genomic data into clinically actionable and hypothetical recommendations for the treatment of individual patients. The pipeline produces two reports: a panel-like report that contains known SNVs and fusions with therapeutic relevance from a collection of more than 4000 events, and a second comprehensive and manually curated report to fully characterize the tumor using the whole genome and transcriptome datasets. Genomic data are presented and discussed at a multidisciplinary molecular tumor board consisting of medical oncologists, pathologists, bioinformaticians, geneticists, and biologists. This approach has enabled clinicians to make informed clinical decisions based on the genomic data integrated with other clinical features, as well as to form new treatment-related hypothesis. POG has shown that use of both whole genome and transcriptome sequencing allows identification of therapeutic targets in a significant proportion of patients. Almost 80% cases were found to have one or more actionable alterations (100% in pediatric cases), and almost one-third of these are defined only using RNA data. Based on molecular tumor board discussion, patients are directed to clinical trials, positioned to genomically informed standard-of-care options, or treated with off-label drugs. With demonstrated effectiveness, the integrative approach developed by POG not only provides molecular insight and treatment options into individual tumors, but also provides a rich resource of molecular data with matched clinical information that will aid our understanding of tumor biology and therapy response mechanisms to inform treatment strategies in the future.
Citation Format: Yaoqing Shen, Martin R. Jones, Erin Pleasance, Melika Bonakdar, Carolyn Ch'ng, Caralyn Reisle, Laura Williamson, Elisa Majounie, Greg Taylor, Simon Chan, Brandon Pierce, Wei Zhang, Amir Muhammadzadeh, Eric Y. Zhao, Dustin Bleile, Karen Mungall, Nina Thiessen, Eric Chuah, Tina Wong, Richard Corbett, Yussanne Ma, Richard A. Moore, Andrew J. Mungall, Yongjun Zhao, Stephen Yip, Anna F. Lee, Rod Rassekh, Rebecca Deyell, Howard Lim, Daniel Renouf, Robyn Roscoe, Steven J.M Jones, Janessa Laskin, Marco A. Marra. Clinical application of whole genome and transcriptome sequencing in cancer care abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A184.
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