tbuckley/cabot-search huggingface dataset:
Abstract B026: Infant ALL without KMT2A rearrangements harbor clinically relevant alterations and share common origins with childhood ALL
Authors: Matthew Zatzman, Jennifer Seelisch, Federico Comitani, Fabio Fuligni, Scott Davidson, Kyoko E. Yuki, Lisa-Monique Edwards, Ledia Brunga, Erin Guest, Stephen P. Hunger, Mignon L. Loh, Elizabeth A. Raetz, John Chen, Jack Bartram, Johann K. Hitzler, Patrick A. Brown, Sumit Gupta, Adam Shlien
Journal: Cancer Research (2024)

Abstract Infant acute lymphoblastic leukemia (ALL) is characterized by high frequency of rearrangements in KMT2A (KMT2Ar), associated with poor outcomes. Infants lacking KMT2Ar typically have superior outcomes, but remain understudied. Here, we use whole genome and transcriptome sequencing to define driver mutations and transcriptional phenotypes in non-KMT2Ar infant ALL. Based on two index cases, we initially suspected that some infants with high-risk clinical features harbored clinically undetected non-canonical alterations to the KMT2A gene; however, we find no such evidence in our data. Instead, we find that these infants acquire other clinically relevant features such as Ph-like expression signatures, fusions impacting ZNF384, TCF3, ETV6::RUNX1, PAX5 or NUTM1, and events in known tumor genes such as CDKN2A, NOTCH1, and others. By mapping transcriptional profiles between infant and childhood B-ALL, we find that - in the absence of KMT2Ar - infant ALL resembles well defined childhood B-ALL subtypes, sharing the same genetic drivers. NUTM1 fusions are particularly enriched in infants compared to older children, and are associated with decreased MHC-Class II expression and B-cell developmental signaling pathways. Ph-like transcriptional signatures were apparent in several infants and confirmed by machine learning driven classification. Overall, our data support a common developmental origin of ALL without KMT2Ar in infants and children. Citation Format: Matthew Zatzman, Jennifer Seelisch, Federico Comitani, Fabio Fuligni, Scott Davidson, Kyoko E. Yuki, Lisa-Monique Edwards, Ledia Brunga, Erin Guest, Stephen P. Hunger, Mignon L. Loh, Elizabeth A. Raetz, John Chen, Jack Bartram, Johann K. Hitzler, Patrick A. Brown, Sumit Gupta, Adam Shlien. Infant ALL without KMT2A rearrangements harbor clinically relevant alterations and share common origins with childhood ALL [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B026.
Abstract B046: Addressing inequities in pediatric solid tumors: Insights from Hispanics in Puerto Rico
Authors: Carolyn M. Ruiz-Perez, Rocío K. Rivera-Valentín
Journal: Cancer Research (2024)

Abstract Introduction: Pediatric solid tumors are a diverse group of rare cancers that occur in children. Recent advancements in therapy, such as immunotherapy, targeted therapy, and precision medicine, have shown promise in improving treatment outcomes for these cancers. Moreover, health disparities in the incidence and mortality rates of pediatric solid tumors have been reported between US racial/ethnic groups, where Hispanics and African ethnicities present higher rates of incidence and metastatic disease. Despite disparities observed in pediatric solid tumors among US Hispanics, no information exists for Puerto Rican Hispanic children with cancer. Thus, this study aims to understand and describe the epidemiology of a Hispanic population of pediatric patients diagnosed with solid tumors living in Puerto Rico. Methods: Age-adjusted incidence rates (IR) and mortality rates (MR) for specific childhood cancers (ages 0-19) were estimated using data obtained from the Incidence Case File from the Puerto Rico Central Cancer Registry for the period 2009-2020. Results: During this period, 666[MS1]pediatric patients were diagnosed with cancer, with malignant bone tumors comprising 4.7% of cases and with an age-adjusted incidence rate of 6.0 cases per million. Among pediatric patients with malignant bone tumors, 34.6% presented with regional disease and 23.1% presented with distant metastatic disease at diagnosis. The mortality rate for pediatric cancers involving bone and joints was 2.4 cases per million. Conclusions: This is a first-of-its-kind analysis in a Hispanic cohort of pediatric solid tumor patients in Puerto Rico. Understanding the disparities in solid pediatric tumors within this Hispanic population is crucial for developing targeted interventions that improve diagnosis, treatment, and survival rates for these children who face other disparities, including limited access to specialized care and economic barriers, among others. Publishing this data is essential as it raises awareness, guides resource allocation, and informs policy decisions to address healthcare inequities. Future studies should explore risk factors and differential gene expression. Acknowledgement: The authors extend gratitude to the Biostatistics and Bioinformatics Core of the UPR Comprehensive Cancer Center and the PR Central Cancer Registry for collaborating in our research. Citation Format: Carolyn M. Ruiz-Perez, Rocío K. Rivera-Valentín. Addressing inequities in pediatric solid tumors: Insights from Hispanics in Puerto Rico [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B046.
Abstract B017: Aberrant translation of microproteins as a source of new cancer dependencies in medulloblastoma
Authors: John Prensner, Pratiti Bandopadhayay, Soumik Saha, Leslie Lupien, Seung H. Choi
Journal: Cancer Research (2024)

Abstract A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation.Dysregulation of ribosome activity not only influences known protein-coding genes, but also unannotated small open reading frames (sORFs) as well.We have recently shown that sORFs may produce functional microproteins in medulloblastoma.Here, we performed an integrative analysis of medulloblastoma patient samples and cell lines.We used ribosome profiling, RNAseq, and mass spectrometry to delineate dysregulation of microprotein production.We employed cell models of MYC overexpression to determine the role of MYC in selective translation of microproteins in medulloblastoma, finding specific associations with upstream open reading frames (uORFs) located in gene leader sequences.We then designed a step-wise approach to define functional microproteins in medulloblastoma through the use of CRISPR/Cas9 screens, saturation mutagenesis, and base editing.We observed distinctive signatures of microprotein bioactivity based on the molecular drivers of medulloblastoma according to disease subtypes.In the Group 3 subtype, we observed an enrichment for bioactive uORFs relative to other disease settings.We then characterized several key microprotein dependencies resulting from uORFs including a molecular mechanism for one candidate, ASNSD1-uORF, in mediating protein-RNA dyssynchrony in Group 3 medulloblastoma.Protein-RNA dyssynchrony is the divergent regulation of protein abundance from RNA abundance, and is a hallmark of Group 3 medulloblastoma.We probed the clinical and therapeutic implications of protein-RNA dyssynchrony and determined that this process may be associated with patterns of drug sensitivity and resistance in medulloblastoma.With this insight, we have now used ASNSD1-uORF to stratify medulloblastoma resistance patterns to inhibitors of RNA transcription.We determine that an interplay between RNA translational control and RNA transcriptional control, while driving resistance in some settings, may also reveal additional drug targets, such as cyclin-dependent kinases.Our findings underscore the fundamental importance of sORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets and therapeutic insights. Citation Format: John Prensner, Pratiti Bandopadhayay, Soumik Saha, Leslie Lupien, Seung H. Choi. Aberrant translation of microproteins as a source of new cancer dependencies in medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B017.
Abstract A072 The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma
Authors: Yueyang Wang, Qiqi Yang, Chuan Yan, David M. Langenau
Journal: Cancer Research (2024)

Abstract Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation for adolescent rhabdomyosarcoma (RMS) muscle cancers. Unfortunately, resistance to OT has been reported in other cancers, with no counterstrategies available. Using preclinical mouse xenograft experiments, we show that OT is effective at curbing RMS growth, yet a subset of tumors develop resistance that is associated with transcriptomic changes that occur in the absence of recurrent genomic mutation. Importantly, a vast majority of resistant RMS models upregulate the PIK3CA/AKT pathway, which in turn activates NRF2 transcription factor phosphorylation and subsequent transcriptional expression of multidrug resistance ABC transport proteins that rapidly efflux drugs from cells. Using dynamic real-time imaging of tumor growth and assessing drug responses at single-cell resolution in human cell line models, we found that the PIK3CA inhibitor alpelisib re-sensitized resistant RMS cells to OT therapy by suppressing the expression of ABC transport proteins. Excitingly, RMS uses the same PIK3CA/AKT pathway activation to drive resistance to standard-of-care combination therapy vincristine, actinomycin D, and cyclophosphamide (VAC) and the combination of OT + alpelisib effectively killed VAC-resistant RMS. Alpelisib also re-sensitized resistant RMS to chemotherapy in preclinical xenograft mouse models resulting in reduced tumor burden and extended disease-free survival. Our work defines a common resistance pathway in RMS and has credentialled a new preclinical strategy to kill therapy-resistant RMS. Citation Format: Yueyang Wang, Qiqi Yang, Chuan Yan, David M. Langenau. The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A072.
Abstract A051 Genome-wide CRISPR/Cas9 library screening identified TP53 as a critical driver for resistance to EZH2 inhibitor in rhabdoid tumors
Authors: Céline Chauvin, Tiphaine Hery, Rachida Bouarich, Fariba Nemati, Diego Teyssonneau, Camille Fouassier, Chiara Giudiceandrea, Zhi-Yan Han, Sakina Zaidi, Didier Surdez, Sergio Roman-Roman, Didier Decaudin, Raphaël Margueron, Franck Bourdeaut
Journal: Cancer Research (2024)

Abstract Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies which occur in kidney, soft-parts and brain. They are characterized by a complete inactivation of the SMARCB1 tumor suppressor gene encoding a core subunit of the chromatin remodeling SWI/SNF complex. Prognosis for children with RTs is poor as, in many instances, these tumors are resistant to conventional type chemotherapy. Pharmacological inhibition of EZH2 is a promising strategy to treat some tumors with loss of function in SMARCB1. However, the clinical response rate remains low, and both primary and secondary resistance have been reported. Understanding the mechanisms of resistance to EZH2 inhibition may allow new therapeutic hypothesis. For this purpose, we realized a genome-wide CRISPR-Cas9 knockout screening on two rhabdoid cell lines treated with EZH2 inhibitor. We identified TP53 loss as the sole consistent gene knock-out able to confer some resistance to EZH2 inhibition in both cell lines. Conversely, we demonstrated that MDM2/MDM4 inhibition, in a TP53-dependant manner, strongly synergized with EZH2 inhibition to control cell lines viability in vitro. We further treated 4 rhabdoid patient-derived xenografts with UNC1999, Idasanutlin and the combination of both and observed a potent tumor growth control upon combined EZH2 and MDM2/MDM4 inhibitions. To conclude, our results strongly encourage to assess the actual efficacy of combined MDM2/MDM4 and EZH2 inhibitors in the treatment of patients with SMARCB1-deficient rhabdoid tumors. Citation Format: Céline Chauvin, Tiphaine Hery, Rachida Bouarich, Fariba Nemati, Diego Teyssonneau, Camille Fouassier, Chiara Giudiceandrea, Zhi-Yan Han, Sakina Zaidi, Didier Surdez, Sergio Roman-Roman, Didier Decaudin, Raphaël Margueron, Franck Bourdeaut. Genome-wide CRISPR/Cas9 library screening identified TP53 as a critical driver for resistance to EZH2 inhibitor in rhabdoid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A051.
Abstract A052 Project HOPE: A spatiotemporal single-cell landscape of high-grade gliomas in children, adolescents and young adults
Authors: Sara G. Danielli, Sina Neyazi, Olivia A. Hack, Li Jiang, Costanza Lo Cascio, Andrezza Nascimento, Cuong Nguyen, Jacob Rozowsky, Ilon Liu, Owen Hoare, Karin Shamardani, Kennedy Cunliffe-Koehler, Johannes Gojo, Keith L. Ligon, Lissa Baird, Sanda Alexandrescu, Jennifer Cotter, Michael Prados, Adam Resnick, Lin Wang, Michelle Monje, Aaron Diaz, Mariella G. Filbin
Journal: Cancer Research (2024)

Abstract Despite the growing insights into the cellular heterogeneity of pediatric brain tumors, the transcriptional changes and spatial reorganization during disease progression remain largely unexplored. Here, we present an in-depth single-cell and 10X Xenium spatial transcriptomic characterization of 24 matched pediatric high-grade gliomas (pHGGs) in children, adolescents and young adults (AYA) profiled at both diagnosis and recurrence - constituting a total of 55 tissue samples. By stratifying the transcriptional programs activated at recurrence, we identify two distinct global response sets. Hemispheric AYA tumors predominantly exhibit upregulation of extracellular matrix pathways at recurrence, whereas midline tumors preferentially activate generic stress response programs. On a cellular level, we find that heterogeneity within the malignant tumor compartment remains largely unchanged at recurrence. However, a subset of AYA patients with hemispheric pHGG shows enrichment of the neural-progenitor-like (NPC-like) tumor cell state, and compositional changes in the immune and normal cell landscape, characterized by a global decrease in myeloid cells and an increase in oligodendrocyte fractions. Those changes lead, in turn, to enhanced NPC-like tumor cell-to-oligodendrocyte interactions. Spatial analysis of our extensive cohort at unprecedented subcellular resolution further reveals distinct cellular and spatial features associated with tumor progression, particularly in the remodeling of cell-cell interactions and tumor cell neighborhoods. Overall, this study provides a comprehensive longitudinal single-cell and spatial atlas of pHGG, uncovering the extensive cellular heterogeneity associated with tumor progression. Our findings highlight the role of intrinsic and extrinsic tumor adaptations in shaping disease progression in pHGG, offering potential novel therapeutic targets. Citation Format: Sara G. Danielli, Sina Neyazi, Olivia A. Hack, Li Jiang, Costanza Lo Cascio, Andrezza Nascimento, Cuong Nguyen, Jacob Rozowsky, Ilon Liu, Owen Hoare, Karin Shamardani, Kennedy Cunliffe-Koehler, Johannes Gojo, Keith L. Ligon, Lissa Baird, Sanda Alexandrescu, Jennifer Cotter, Michael Prados, Adam Resnick, Lin Wang, Michelle Monje, Aaron Diaz, Mariella G. Filbin. Project HOPE: A spatiotemporal single-cell landscape of high-grade gliomas in children, adolescents and young adults [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A052.
Abstract PR007: Persistent poverty is associated with risk of early mortality among children with cancer: An analysis of SEER data
Authors: Emma Hymel, Josiane Kabayundo, Krishtee Napit, Shinobu Watanabe-Galloway
Journal: Cancer Research (2024)

Abstract Objectives: Social determinants of health are understudied in the context of pediatric cancer. Persistent poverty, a measure developed by the National Cancer Institute and the US Department of Agriculture’s Economic Research Service, is defined as having 20% or more of an area’s population having lived below the poverty level for a period of about 30 years. The effect of persistent poverty on pediatric cancer outcomes is not well understood. Methods: This population-based longitudinal study uses data from the Surveillance, Epidemiology, and End Results (SEER)-22 registries Incidence Data with Census Tract Attributes Database. All primary cases of malignant cancer diagnosed among children aged 0-19 at diagnosis from 2006-2020 were included. Early mortality was defined as death within three months of diagnosis. Cox proportional hazards models were used to compute crude and adjusted hazard rations (aHRs) for the association between persistent poverty and early mortality. Based on a directed acyclic graph, models were also adjusted for age, sex, race/ethnicity, cancer type, and rurality (defined using Rural Urban Commuting Area codes). Results: The study included 97,132 children; 12.63% resided in a persistent poverty census tract at diagnosis and 1.66% died within three months of diagnosis. In the adjusted model, living in a persistent poverty census tract was associated with a higher risk of early mortality (aHR=1.26, 95% CI: 1.10-1.45). Additionally, a higher risk of early mortality was observed among Non-Hispanic Black (aHR=1.44, 95% CI: 1.23-1.70), Non-Hispanic Asian and Pacific Islander (aHR=1.39, 95% CI: 1.15-1.68), and Hispanic children (aHR=1.33, 95% CI: 1.18-1.49) compared to Non-Hispanic White children. Children residing in rural areas also had a higher risk of death compared to children in urban areas (aHR=1.29, 95% CI: 1.11-1.50). In sensitivity analyses looking at the effect of persistent poverty on risk of death within one month of diagnosis, a similar effect size was observed (aHR=1.26, 95% CI: 1.07-1.48). Conclusions: Our study observed an increased risk of early mortality among children living in persistent poverty census tracts and among racial/ethnic minorities. Future studies should explore potential mediators of the association between persistent poverty and early mortality, including health insurance, treatment access, and individual-level socioeconomic status. Citation Format: Emma Hymel, Josiane Kabayundo, Krishtee Napit, Shinobu Watanabe-Galloway. Persistent poverty is associated with risk of early mortality among children with cancer: An analysis of SEER data [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr PR007.
Abstract B020: Improved outcome for patients with alternative lengthening of telomeres (ALT) neuroblastoma randomized to tandem myeloablative therapy on COG ANBL0532
Authors: Balakrishna Koneru, Trevor Burrow, Kristyn McCoy, Jonas Nance, Arlene Naranjo, Fan F. Zhang, Meredith S. Irwin, Julie R. Park, C. Patrick Reynolds
Journal: Cancer Research (2024)

Abstract Background: Overall survival (OS) of high-risk neuroblastoma (HRNB) patients with alternative lengthening of telomeres (ALT) tumors (∼23% of patients) is low. Event-free survival (EFS) of HRNB patients in COG ANBL0532 was higher for tandem relative to single ASCT.We sought to determine if ALT HRNB patients on ANBL0532 benefited from tandem ASCT. Methods:We assessed telomere maintenance mechanisms (TMM), defined as per Cancer Res 80:2663, 2020, in 204 primary tumors from ANBL0532 patients as TERT+ (high TERT mRNA), ALT (positive for telomeric DNA C-circle assay) or ultrabright telomere foci (UTF), or no TMM. Due to non-proportional hazards, survival comparisons used the Improved Two-Stage Procedure (J Stat Comput Simul. 2017; 87:1877). Results: TMM status was: ALT n=48 (23.5%), TERT+ n=140 (68.6%), TMM negative n=16 (7.8%). Patients with TERT+ tumors more frequently progressed early, but 8-year OS was superior for TERT+ compared to ALT (58.1±4.6% vs 41.6±8.2%; p=0.0007), while 8-year OS for TMM negative was 67.7±12.2%. The 8-year OS for TERT+ patients randomized to single (n=67) vs tandem (n=59) ASCT was 56.9±6.7% vs 71.8±6.5% (p=0.32) and for ALT patients randomized to single (n=20) vs tandem (n=19) ASCT was 26.9±11.5% vs 61.1±13.5% (p=0.011).For patients on ANBL0532 who received dinutuximab post-consolidation therapy, the 8-year OS for TERT+ patients who underwent single (n=52) vs tandem (n=43) ASCT was 53.5±7.6% vs 75.8±7.8% (p=0.10) while for ALT patients who underwent single (n=13) vs tandem (n=10) ASCT it was 23.1±14.3% vs 77.8±16.4% (p=0.022). Conclusions:As previously reported, patients with ALT HRNB have inferior OS relative to TERT+ HRNB.TMM negative HRNB patients had apparently higher OS than ALT or TERT+ but small numbers preclude formal analyses. OS was significantly improved in ALT HRNB by tandem ASCT.These data support use of tandem myeloablative therapy for patients with ALT neuroblastoma until effective targeted therapies become available. Citation Format: Balakrishna Koneru, Trevor Burrow, Kristyn McCoy, Jonas Nance, Arlene Naranjo, Fan F. Zhang, Meredith S. Irwin, Julie R. Park, C. Patrick Reynolds. Improved outcome for patients with alternative lengthening of telomeres (ALT) neuroblastoma randomized to tandem myeloablative therapy on COG ANBL0532 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B020.