Increasing availability of genomic testing poses new challenges to clinicians, particularly where variant interpretation from commercial sources may be equivocal. We report a patient with recurrent rhabdomyosarcoma and subsequent bilateral breast cancer who was found to harbor a previously undescribed germline TP53 sequence alteration annotated by the commercial laboratory as a variant of uncertain significance (VUS). By investigating publically available databases of aggregated normal germline and malignant somatic genomic sequences, we conclude that this missense variant, c.476C>T (p.A159V), is a novel, pathogenic Li-Fraumeni syndrome mutation, and illustrate the utility of these resources in clinical pediatric hematology and oncology practice.
Increasing availability of genomic testing poses new challenges to clinicians, particularly where variant interpretation from commercial sources may be equivocal. The authors report a patient with recurrent rhabdomyosarcoma and subsequent bilateral breast cancer who was found to harbor a previously undescribed germline TP53 sequence alteration annotated by the commercial laboratory as a variant of uncertain significance. By investigating publicly available databases of aggregated normal germline and malignant somatic genomic sequences, the authors conclude that this missense variant, c.476C>T (p.A159V), is a novel, pathogenic Li-Fraumeni syndrome mutation and demonstrate the utility of these resources in clinical pediatric hematology and oncology practice.
Abstract Primary superficial Ewing sarcoma (psES) cases are exceedingly rare, with fewer than 150 cases reported in the literature. Small case series have suggested differences between psES and Ewing sarcoma (ES) of bone or deep soft tissues: psES appears to have a more indolent course and a higher 5‐year overall survival rate. PsES is more common in older adolescent females as opposed to younger males in their peak growth velocity years in bone or deep soft tissue ES. We present a case report of a 17‐year‐old female with a relatively static nodule on her left thigh for 4 years. Morphologic, immunohistochemical, and molecular evaluations confirmed ES. Patient underwent a gross‐total resection and a shortened course of adjuvant chemotherapy without radiation. Cancer gene panel testing found three gene abnormalities (in addition to EWSR1‐FLI1 fusion): CCND1 copy number gain, ELF3 copy number loss, and TNFRSF14 copy number loss. To our knowledge, this is the first published case report of psES to include genomic sequencing and the first to report ELF3 and TNFRSF14 abnormalities in ES. Larger series of psES cases with genomic profiling are needed to elucidate a possible genetic etiology for its more indolent clinical course and favorable outcomes.
Abstract Introduction: MYCN amplification is the genetic aberration most consistently associated with poor outcomes in alveolar rhabdomyosarcomas (aRMS) and neuroblastoma (NBL). It regulates key oncogenic processes including tumor cell survival, proliferation and metastasis. In aRMS, MYCN transcription is driven by the PAX3-FOXO1 gene fusion. MYCN and other short half-life mRNA transcripts depend on CDK9 to drive transcription of target genes to initiate and maintain the oncogenic program, making CDK9 blockade an effective therapeutic route against MYC-driven cancers. We have previously shown the activity and tolerability of enitociclib in tumor xenograft models. In this study, we investigated the activity of the selective small-molecule CDK9 inhibitor enitociclib (VIP152/BAY1521152) in preclinical models of pediatric MYCN-amplified aRMS and NBL. Methods: Cell-based viability assays were performed in aRMS (Rh30 and Rh41) and NBL (LAN1, SK-N-AS, SK-N-BE(2) and SK-N-MC) cell lines. Enitociclib antitumor activity was measured by Alamar Blue cell viability assay after 96 h exposure at 9 dose levels (8 nM-2 μM) with DMSO used as control. We performed combination screens of enitociclib with several FDA-approved drugs (n=215). Selected agents with IC50 values <1 μM were analyzed at constant dilution ratios of two inhibitors. Drug synergy was calculated by established methods using SynergyFinder 3.0. Target modulation was determined for RNA polymerase II (RNAPII), MYCN and apoptosis inducers caspase-3 and PARP, in addition to PAX3-FOXO1 and PLK1 protein levels in aRMS cells, by western blotting after continuous exposure with enitociclib for 24 h. Results: Significant cytotoxic activity, with IC50 values ranging from 48-182 nM and 39-123 nM was seen for aRMS cells and NBL cells, respectively. SynergyFinder found synergistic effects of enitociclib with irinotecan, carfilzomib, etoposide, bortezomib, selinexor or topotecan tested at clinically relevant concentrations in the aRMS cell line Rh41. Enitociclib induced apoptosis with cleavage of caspase-3 and PARP by western blotting in a dose- and time-dependent manner in addition to the depletion of phosphorylated RNAPII (Ser2) and MYCN protein levels. In aRMS cells, PAX3-FOXO1 fusion and PLK1 proteins were downregulated. Annexin V/propidium iodide staining confirmed a dose-dependent increase in apoptosis after enitociclib exposure. Conclusions: Our results suggest that CDK9 inhibition is potentially clinically relevant for MYCN-amplified solid tumors such as aRMS and NBL due to its significant antitumor activity and pharmacologic targetability. The data provide essential information on the distinct targets, biomarkers of activity and clinically feasible drug combinations for the development of enitociclib in clinical trials addressing an unmet need in pediatric oncology. Citation Format: Son Tran, Patrick Sipila, Melanie M. Frigault, Amy J. Johnson, Joseph Birkett, Raquel Izumi, Ahmed Hamdy, Beatrix Stelte-Ludwig, David P. Douglass, Anne-Marie Langevin, Norman J. Lacayo, Aru Narendran. Targeting CDK9 via the small-molecule inhibitor enitociclib as a therapeutic strategy to treat MYCN-amplified rhabdomyosarcoma and neuroblastoma in children [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1558.
In retrospective analyses, the Pediatric Oncology Group [POG) and the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) histologic grade predict outcome in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), but prospective data on grading, clinical features, and outcomes of low-grade NRSTS are limited.
Abstract Survival outcomes for patients with neuroblastoma vary markedly and reliable prognostic markers and risk stratification tools are lacking. We sought to identify and validate a transcriptomic signature capable of predicting risk of mortality in patients with neuroblastoma. The TARGET NBL dataset (n = 243) was used to develop the model and two independent cohorts, E-MTAB-179 (n = 478) and GSE85047 (n = 240) were used as validation sets. EFS was the primary outcome and OS was the secondary outcome of interest for all analysis. We identified a 21-gene signature capable of stratifying neuroblastoma patients into high and low risk groups in the E-MTAB-179 (HR 5.87 [3.83–9.01], p < 0.0001, 5 year AUC 0.827) and GSE85047 (HR 3.74 [2.36–5.92], p < 0.0001, 5 year AUC 0.815) validation cohorts. Moreover, the signature remained independent of known clinicopathological variables, and remained prognostic within clinically important subgroups. Further, the signature was effectively incorporated into a risk model with clinicopathological variables to improve prognostic performance across validation cohorts (Pooled Validation HR 6.93 [4.89–9.83], p < 0.0001, 5 year AUC 0.839). Similar prognostic utility was also demonstrated with OS. The identified signature is a robust independent predictor of EFS and OS outcomes in neuroblastoma patients and can be combined with clinically utilized clinicopathological variables to improve prognostic performance.
Abstract Congenital/neonatal bone neoplasms are extremely rare. We present the case of a patient with a neonatal bone tumor of the fibula that had osteoblastic differentiation and a novel PTBP1::FOSB fusion. FOSB fusions are described in several different tumor types, including osteoid osteoma and osteoblastoma; however, these tumors typically present in the second or third decade of life, with case reports as young as 4 months of age. Our case expands the spectrum of congenital/neonatal bone lesions. The initial radiologic, histologic, and molecular findings supported the decision for close clinical follow‐up rather than more aggressive intervention. Since the time of diagnosis, this tumor has undergone radiologic regression without treatment.
