Citations

Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome.

PURPOSE Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. PATIENTS AND METHODS In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. RESULTS Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. CONCLUSION Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.

Background: The FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Gilt) improves survival compared with standard salvage chemotherapy in relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML); however, relapses are common and long-term survival remains poor. Combination therapies of FLT3 tyrosine kinase inhibitors (TKIs) with agents that induce apoptosis have demonstrated preclinical synthetic lethality and enhanced cytotoxicity against FLT3mut+ clones. This may delay or prevent drug resistance. We present updated data from the dose-escalation and expansion cohorts of an ongoing, multicenter, open-label, Phase 1b trial (NCT03625505) of Gilt in combination with B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Ven) in patients (pts) with R/R FLT3mut+ AML. Methods: Pts with R/R AML with ≥1 prior line of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible. The expansion cohort required FLT3mut+ R/R AML at enrollment. Pts received the recommended Phase 2 dose (RP2D) of Ven 400 mg in combination with Gilt 120 mg daily in 28-day cycles, following a 3-day ramp-up of Ven. Pts with prior Gilt were excluded from expansion, and none were enrolled in dose escalation; prior Ven or other FLT3 inhibitor was permitted. Concurrent use of moderate or strong CYP3A4 inhibitor was allowed. Interruptions of Ven or both drugs simultaneously were permitted for management of adverse events (AEs), and subsequent cycles could include dose adjustments to minimize myelosuppression or other drug-related AEs. The primary endpoint was modified composite complete remission (mCRc; complete response [CR] + CR with incomplete platelet recovery [CRp] + CR with incomplete blood count recovery [CRi]) + morphologic leukemia-free state (MLFS). Responses were graded by the International Working Group (IWG) for AML criteria (with adapted CRi criteria as presented in the ADMIRAL trial) for comparison with composite CR (CRc) used in Gilt development. All criteria for response used by IWG were maintained in these response definitions. Secondary endpoints included CR + CR with partial hematologic recovery (CRh) and duration of response (DOR) of mCRc. Results: At data cutoff, April 15, 2020, 39 R/R pts started therapy at the RP2D (internal tandem duplications [ITD] only [n=32]; tyrosine kinase domain [TKD] mutation only [n=5]; both TKD and ITD [n=2]). Median age was 63 years (range 23-85) and the majority had an ECOG status of 1-2 (87.2%). Most pts (n=29; 74.4%) had received ≥2 prior lines of therapy, including ≥1 FLT3 TKI (n=25, 64.1%; midostaurin, n=19; sorafenib, n=5; crenolanib, n=1). Twelve pts (30.8%) had prior stem-cell transplant (SCT); 3 (7.7%) had received prior Ven. Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 37 pts (94.9%), and 28 (71.8%) reported serious AEs. The only Grade 3/4 nonhematologic TEAE reported in >20% of pts was febrile neutropenia (48.7%). Four pts (10.3%) experienced a fatal AE, including colitis, disease progression, multiple organ dysfunction syndrome, and bronchopulmonary aspergillosis (all n=1). AEs leading to Ven and Gilt interruptions occurred in 19 pts (48.7%) and 18 pts (46.2%), respectively, and AEs leading to dose reductions occurred in 2 pts (5.1%) for each treatment. Six pts (15.4 %) and 5 pts (12.8%) discontinued Ven and Gilt, respectively, owing to AEs. mCRc was achieved by 83.8% of pts (n=31/37; Table). With median duration of follow-up of 2.9 (range 0.8−11.0) months in all pts, median event-free survival was 5.1 (95% confidence interval: 2.8, 8.3) months but administrative censoring after short follow-up for a large number of recently enrolled patients limits interpretation; median DOR has not been reached. Eight pts (21.6%), all ITD only, proceeded to SCT. CR + CRh was achieved by 7 pts (18.9%). Conclusions: Ven plus Gilt achieved a very high overall rate of marrow and blood blast elimination and mCRc rate (84%) in this expansion cohort of heavily pretreated FLT3mut+ pts, the majority of whom had prior FLT3 TKI exposure. Using similar response assessment criteria, the high mCRc rate here suggests substantially greater antileukemic activity from Ven plus Gilt compared with single-agent Gilt. Cytopenias were prominent but manageable with dose interruption/modification on subsequent cycles. Nonhematologic toxicities were modest, and the combination was well tolerated. Disclosures Daver: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Altman:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Agios, Theradex, Abbvie: Other: Advisory Board; Astellas, Agios: Honoraria, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Patents & Royalties: Scientific Advisory Board - no payment accepted; Biosight: Other: No payment but was reimbursed for travel . Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Ritchie:Abbvie: Honoraria; Sierra Oncology: Honoraria; Incyte: Speakers Bureau; Novartis: Honoraria; Jazz pharmaceuticals: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. McCloskey:Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Smith:Abbvie: Other: Research Support, Research Funding; Sanofi: Honoraria; Astellas Pharma: Honoraria, Other: Research Support, Research Funding; FujiFilm: Other: Research support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria. Schiller:Johnson & Johnson: Current equity holder in publicly-traded company; Novartis: Consultancy, Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Genentech-Roche: Research Funding; Geron: Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Celator: Research Funding; FujiFilm: Research Funding; Ariad: Research Funding; Constellation: Research Funding; Cyclacel: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Astellas Pharma: Honoraria, Research Funding; Actinium: Research Funding; Gamida: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Daiichi Sankyo: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Forma: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Sanofi: Speakers Bureau. Bradley:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Qin:AbbVie: Current Employment, Other: may hold stock or other options. Dilley:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Perl:Leukemia & Lymphoma Society.: Other; AbbVie Inc, Astellas, Actinium, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo Inc, FUJIFILM Pharmaceuticals USA Inc: Research Funding; AbbVie Inc, Actinium Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc, FORMA Therapeutics, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, NewLink Genetics: Other; AbbVie Inc, Arog Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc: Consultancy; Astellas, AbbVie Inc, Daiichi Sankyo, Actinium, Forma, Syndax, Loxo: Consultancy, Honoraria. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test.

Introduction: MM is an incurable disease with risk categorizations by cytogenetic abnormalities. Prognostic implications of chromosome translocation t(11;14)+ are important to inform development of biomarker-targeted therapies such as the B-cell lymphoma-2 (BCL-2) pathway inhibitors. This study aims to evaluate MM treatment (Tx) patterns and outcomes of t(11;14)+ compared with other cytogenetic cohorts in US routine clinical practice. Methods: A retrospective observational cohort study of the Flatiron Health database, which comprises de-identified electronic health record-derived patient (pt)-level data from over 280 community and academic cancer clinics in the US. Pts aged ≥18 years who received a first-line (1L) induction Tx within ≤60 days of MM diagnosis from 1/1/2011 to 1/31/2020, and were not enrolled in a clinical trial were identified at the start of each Tx line (index date) and followed up (f/u) until 1/31/2020. Only cytogenetic results by fluorescence in situ hybridization (FISH) were used to stratify the cohort into: t(11;14)+; standard risk, excluding t(11;14)+ (SR); and high risk, (HR; del 17p, t(4;14), t(14;16), t(14;20), chromosome 1 abnormalities as a proxy for 1q gain; and t(11;14) where it co-occurs). Descriptive analyses of pt characteristics and Tx were conducted. Kaplan-Meier analyses were used to evaluate median time to next treatment (TTNT) and overall survival (OS) with log-rank test for significance. The cohort was stratified by age ≤70/>70 years (yrs) as a proxy for transplant eligibility. Results: Of 10,703 pts with MM in the database, 5982, 3059 and 1595 pts were eligible for 1L, second-line (2L), and third-line (3L) analysis, of which 76%, 84%, and 86%, respectively, had FISH test results before Tx initiation. 14% of pts with FISH test results were t(11;14)+, ~55% SR and ~35% HR. Included pts were predominately male (55%), ~90% treated in the community setting and ~16% African-American. Pts in the 3L cohort were younger at diagnosis with a median age (interquartile range) of 67 (59 ̶ 74) yrs compared with 69 (61 ̶ 76) yrs in both 1L and 2L. The 1L Tx pattern was consistent across cytogenetic cohorts with bortezomib (V), lenalidomide (R), dexamethasone (d) as the most common Tx (>42%). Together, VRd, Rd, Vd, and cyclophosphamide (Cy) in combination with Vd represented ≥90% of 1L Tx (Figure 1). Across 2L cytogenetic cohorts, the most common Tx regimens (≥25%) were VRd and Rd. The use of regimens containing carfilzomib (K) and daratumumab (D) was emerging in 2L: KRd in 8% of t(11;14)+ and HR and 5% in SR; Kd 5% in all groups; DRd in 4% of t(11;14)+ and 3% in SR and HR (Figure 1). 3L Tx pattern was fragmented with different Tx regimens. Rd was the most common 3L Tx option: 9% in t(11;14)+, 10% in SR and 7% in HR (Figure 1). Across all lines of Tx, t(11;14)+ had similar Tx outcomes to SR, and HR had poorest outcomes (Table 1). Pts TTNT shortened as they advanced to later lines of Tx (Table 1). Although TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts, especially in 1L where transplant in those ≤70 yrs vs >70 yrs at diagnosis was 44% vs 11% for t(11;14)+, 47% vs 10% for SR and 49% vs 9% for HR. Conclusions: This study identified cytogenetic subgroups across 1L to 3L in a predominately community setting in the US. MM t(11;14)+ pts had similar 1L and 2L Tx patterns to SR and HR. Across all lines of Tx, the outcomes of t(11;14)+ and SR pts were comparable and better than HR pts. TTNT was reduced as pts advanced to later lines of Tx. Pts continuing to 3L Tx were younger at diagnosis, but there was not a clear-cut standard of care. While TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts. This study sets the benchmark for novel treatment options, such as BCL-2 pathway inhibitors, primarily wherever available biomarker-driven therapy is considered appropriate. Disclosures Atrash: Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; BMS, Jansen oncology, Sanofi: Speakers Bureau; Amgen, GSK, Karyopharm.: Research Funding. Flahavan:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Roche Products Ltd.: Current Employment. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Karve:AbbVie: Current Employment, Current equity holder in publicly-traded company. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jirau-Lucca:Genentech, Inc.: Current Employment; AbbVie: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Nixon:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Ailawadhi:Takeda: Honoraria; Pharmacyclics: Research Funding; Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Phosplatin: Research Funding; Amgen: Research Funding; Celgene: Honoraria; Janssen: Research Funding.

Abstract: Coronavirus disease 2019 (COVID-19) first emerged in a group of patients who presented with severe pneumonia in Wuhan, China, in December 2019. A novel virus, now called SARSCoV- 2 (Severe Acute Respiratory Syndrome Coronavirus-2), was isolated from lower respiratory tract samples. The current outbreak of infection has spread to over 100 countries and killed more than 340,000 people as of 25th May, 2020. The predominant clinical manifestation of COVID-19 is a respiratory disease- ranging from mild flu-like symptoms to fulminant pneumonia and Acute Respiratory Distress Syndrome (ARDS). Patients with pre-existing cardiovascular risk factors are considered more susceptible to the virus, and these conditions are often worsened by the infection. Furthermore, COVID-19 infection has led to de novo cardiac complications, like acute myocardial injury and arrhythmias. In this review, we have focused on the cardiovascular manifestations of COVID-19 infection that have been reported in the literature so far. We have also outlined the effect of pre-existing cardiovascular disease as well as risk factors on the clinical course and outcomes of COVID-19 infection.

AbstractMolecular prognostic factors for individualized treatment of squamous cell carcinoma (SCC) are poorly defined. Our study developed and validated a novel molecular tools aid in preinguinal and postinguinal lymphadenectomy risk stratification in node‐positive penile SCC. Patients with node‐positive penile SCC who underwent inguinal or ilioinguinal lymphadenectomy were divided into three cohorts: a discovery set, a development set and a validation set. The local ethics committee approved the study. The primary endpoint was cancer‐specific survival (CSS). At the discovery stage, 17 CpG sites were significantly associated with CSS. In the development set, we constructed a 3‐CpG‐based prognostic score for survival prediction. The hazard ratio (HR) of the panel (dichotomized using the optimal cutoff) was 5.8 in the multivariate analyses (P < .001). The addition of the methylation score significantly improved the pN‐stage C‐index from 0.70 to 0.79 (incremental C = 0.09, P < .001). In the validation set, the methylation panel showed a HR of 9.9 in the multivariate analyses. The addition of the molecular marker improved the pN‐stage C‐index from 0.69 to 0.78 (incremental C = 0.09, P < .001). The methylation score remarkably separated survival curves in different pN stages, which indicate that the tool can be applied to tailor the treatment in both preinguinal and postinguinal lymphadenectomy settings. We developed and validated a prognostic methylation panel for node‐positive penile SCC. The tool may aid in the risk stratification of the population with heterogeneous outcomes and needs prospective validation. Patients in high‐risk group may benefit from more aggressive therapy or clinical trials.

The field of cardiac electrophysiology has been on the cutting edge of advanced digital technologies for many years. More recently, medical device development through traditional clinical trials has been supplemented by direct to consumer products with advancement of wearables and health care apps. The rapid growth of innovation along with the mega-data generated has created challenges and opportunities. This review summarizes the regulatory landscape, applications to clinical practice, opportunities for virtual clinical trials, the use of artificial intelligence to streamline and interpret data, and integration into the electronic medical records and medical practice. Preparation of the new generation of physicians, guidance and promotion by professional societies, and advancement of research in the interpretation and application of big data and the impact of digital technologies on health outcomes will help to advance the adoption and the future of digital health care.

Abstract Sprouting angiogenesis is a highly coordinately process controlled by vascular endothelial growth factor receptor (VEGFR)‐Notch signaling. Here we investigated whether Tripartite motif‐containing 28 (TRIM28), which is an epigenetic modifier implicated in gene transcription and cell differentiation, is essential to mediate sprouting angiogenesis. We observed that knockdown of TRIM28 ortholog in zebrafish resulted in developmental vascular defect with disorganized and reduced vasculatures. Consistently, TRIM28 knockdown inhibited angiogenic sprouting of cultured endothelial cells (ECs), which exhibited increased mRNA levels of VEGFR1, Delta‐like (DLL) 3, and Notch2 but reduced levels of VEGFR2, DLL1, DLL4, Notch1, Notch3, and Notch4.The regulative effects of TRIM28 on these angiogenic factors were partially mediated by hypoxia‐inducible factor 1 α (HIF‐1α) and recombination signal‐binding protein for immunoglobulin kappa J region (RBPJκ). In vitro DNA‐binding assay showed that TRIM28 knockdown increased the association of RBPJκ with DNA sequences containing HIF‐1α‐binding sites. Moreover, the phosphorylation of TRIM28 was controlled by VEGF and Notch1 through a mechanism involving RBPJκ‐dual‐specificity phosphatase (DUSP)‐p38 MAPK, indicating a negative feedback mechanism. These findings established TRIM28 as a crucial regulator of VEGFR‐Notch signaling circuit through HIF‐1α and RBPJκ in EC sprouting angiogenesis.

Abstract The Clinical Genome (ClinGen) Resource is a US National Human Genome Research Institute (NHGRI)-funded program dedicated to building an expert curated and freely available central resource that defines the clinical relevance of genes and variants for use in precision medicine. Teams of experts in various clinical domains come together as working groups within ClinGen to facilitate the interpretation, annotation and utilization of genes-variants for clinical application. Somatic Cancer is one such ClinGen Clinical Domain Working Group (CDWG) that consists of over 90 members worldwide, including clinicians, clinical laboratory diagnosticians, genomic scientists and bioinformaticians. Members of this CDWG identify high priority somatic variants in different cancer types that require expert curation and consensus in their clinical interpretation. In order to accurately implement practice guidelines/standards for variant interpretation, the Somatic Cancer CDWG recently established a somatic Variant Curation Expert Panel (VCEP) approval process. Based on their interest and clinical domain expertise, a subset of the CDWG members formed somatic VCEPs to perform authoritative curation on the shortlisted genes-somatic variants within the context of a disease, therapeutic indication or biological pathway. Expert curation within these VCEPs is performed by utilizing guidelines such as those recommended by AMP/ASCO/CAP (Li et al. 2017) and the Somatic Cancer CDWG (Ritter et al. 2016). Wherever necessary, the somatic VCEPs will develop: 1) gene- and disease-specific modifications to address gaps in existing variant assessment guidelines, 2) quantitative approaches for variant interpretation, and 3) implement standardized protocols for annotating somatic variants in genes for a specific disease, drug or biological pathway. Furthermore, ClinGen recently formed the Cancer Variant Interpretation (CVI) committee to provide support, review and feedback on the provisional somatic variant interpretation proposals developed by the VCEPs. The CVI provides somatic VCEPs with a preliminary approval before the final approval by the ClinGen CDWG oversight committee and ultimately ‘expert panel' status in ClinVar, an NCBI-maintained database of clinically relevant gene variants. NTRK fusions in cancer is the first Somatic VCEP going through the ClinGen Somatic Expert Panel approval process. Alterations in the FGFR pathway in GU cancers is the second somatic VCEP under consideration. The Somatic CDWG uses the CIViC (Clinical Interpretation of Variants in Cancer) platform for curation of somatic variants. To date, the CDWG has curated 268 evidence items relating to cancer variants in CIViC, 6 assertions, and 33 evidence source suggestions. The ultimate goal of the Somatic CDWG is to enhance the usability, dissemination and implementation of cancer somatic changes in the ClinGen resource and other cancer variant knowledgebases. Citation Format: Shruti Rao, Deborah Ritter, Arpad Danos, Gordana Raca, Angshumoy Roy, Kilannin Krysiak, Wan-Hsin Lin, Erica Barnell, Matthew McCoy, Beth Pitel, Dmitriy Sonkin, Jue Wang, Seyed Ali Hosseini, Shamini Selvarajah, Ian King, Rashmi Kanagal-Shamana, Xinjie Xu, Jeremy L. Warner, Funda Meric-Bernstam, Jason D. Merker, Marilyn Li, Alex H. Wagner, Malachi Griffith, Obi L. Griffith, Shashikant Kulkarni, Subha Madhavan. ClinGen somatic cancer working group: Disseminating standardized cancer molecular diagnostic data and evidence through global collaboration and expert curation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3215.

Abstract Introduction: The Clinical Genome Resource (ClinGen) Somatic Working Group (sWG) is a multi-institution team engaged in developing processes, resources, and standards to support accurate classification of somatic variants in cancer. Existing decision support resources in cancer knowledgebases are heavily skewed towards genes and variants relevant in adult cancers; however, information to support variant interpretation in childhood cancers is limited. Here we report on the goals and progress of the Pediatric Cancer Taskforce, created within the ClinGen sWG, to lead curation efforts of actionable alterations in childhood cancers. Methods: The ClinGen sWG Pediatric Cancer Taskforce (PCT) consists of a core group of twelve members comprising geneticists, pathologists, and oncologists with expertise in different pediatric cancers and with representation from 9 leading pediatric institutions. The taskforce has a total of 35 members including volunteer-curators who work under guidance of the expert members. Curation of childhood cancer variants is conducted in collaboration with the Clinical Interpretation of Variants in Cancer (CIViC) team at Washington University in Saint Louis, using the CIViC knowledgebase (civicdb.org) and the ClinVar database as open-access curation and data-sharing platforms. Diagnostic, prognostic, and therapeutic evidence is tiered according to the AMP/ASCO/CAP guidelines for the clinical interpretation of somatic variants. PCT members are assigned specific genetic variant-tumor type associations for curation, which are then reviewed in monthly conferences to finalize assertions in CIViC. Results: The PCT has prioritized 40 genetic alterations relevant to pediatric cancer for curation based on their clinical relevance and the lack of sufficient existing curated evidence in clinical knowledgebases. To date, 4 assertions have been created and added to the database: HEY1-NCOA2 fusion in mesenchymal chondrosarcoma, KIAA1549-BRAF fusion and ACVR1 p.G328V variant in pediatric glioma, and EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia. Active curation has been initiated for NTRK fusions agnostic of tissue histology, targetable kinase fusions in Ph-like B-lymphoblastic leukemia, and common variants in selected pediatric sarcomas and brain tumors, focusing heavily on driver gene fusions in childhood cancers. 119 evidence items have been created in CIViC by the members. The PCT also works to implement more standardized and accurate classification of pediatric cancers in CIViC and other cancer resources, and to enhance search for pediatric-specific data through appropriate tagging of evidence using ontology terms. Conclusions: As molecular alterations are increasingly relevant to the care of children with cancer, the ClinGen PCT will work to develop standards, processes, and resources for efficient and accurate determination of clinical relevance of pediatric cancer variants. Citation Format: Alanna J. Church, Shruti Rao, Deborah Ritter, Arpad Danos, Kilann Krysiak, Laura B. Corson, Kevin E. Fisher, Matthew Hiemenz, Katherine A. Janeway, Jianling Ji, Chimene A. Kesserwan, Theodore W. Laetsch, Donald W. Parsons, Ryan J. Schmidt, Kristen L. Sund, Wan-Hsin Lin, Malachi Griffith, Obi L. Griffith, Shashikant Kulkarni, Subha Madhavan, Angshumoy Roy, Gordana Raca. Curation of pediatric cancer variants within the Clinical Genome Resource (ClinGen) [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A58.