Biology subjects

Crompton, B. D.

Publications and source records attributed to Crompton, B. D..

5 recordsLinked to original sources

bioRxiv2026

Clustered structural variant hotspots enable oncogenic addiction and plasticity in osteosarcoma

The genomic landscape of osteosarcoma, the most common bone cancer worldwide, is among the most structurally complex of all human malignancies. The identification of recurrent and functionally consequential patterns has thus remained a challenge. Across 236 whole-genome sequencing osteosarcoma samples, we uncovered five genomic hotspots of clustered structural variation collectively altered in 58% of tumors. Four were associated with amplification of oncogenes ( MYC , CCND3 , CCNE1 , CDK4) , while the fifth mapped largely upstream of TP53 . Hotspot events showed coordinated patterns of co-occurrence and mutual exclusivity with each other and with tumor suppressor alterations, suggesting genomic context-specific selection. We found localized transcriptional dysregulation at hotspot event loci, and single cells harboring these events converged on a neural crest-like program, linking these structural alterations to a less differentiated cell state. These events were also detectable non-invasively through liquid biopsies and displayed ongoing structural evolution throughout disease progression, a finding with potential clinical utility. Our results provide novel insight into how complex rearrangements shape oncogenesis in osteosarcoma, with broader relevance to other cancers characterized by complex genomes.

cancer biology↗

bioRxiv2025

Detection and monitoring of translocation renal cell carcinoma via plasma cell-free epigenomic profiling

TFE3 translocation renal cell carcinoma (tRCC), an aggressive kidney cancer driven by TFE3 gene fusions, is frequently misdiagnosed owing to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays that detect tumor DNA via somatic mutations or copy number alterations are unsuitable for tRCC, since it often lacks recurrent genetic alterations and because fusion breakpoints are highly variable between patients. We reasoned that epigenomic profiling could more effectively detect tRCC, because the driver fusion constitutes an oncogenic transcription factor that alters gene regulation. By defining a TFE3-driven epigenomic signature in tRCC cell lines and detecting it in patient plasma using chromatin immunoprecipitation and sequencing, we distinguished tRCC from clear cell RCC (AUC=0.87) and healthy controls (AUC=0.91) at low tumor fractions (<1%). This work establishes a framework for non-invasive epigenomic detection, diagnosis and monitoring of tRCC, with implications for other mutationally quiet, fusion-driven cancers. SIGNIFICANCETranslocation renal cell carcinoma (tRCC) is an aggressive fusion-driven subtype of kidney cancer that is frequently misdiagnosed due to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays targeting DNA alterations are suboptimal for use in tRCC due to its paucity of genomic changes. We demonstrate the utility of cell-free chromatin profiling to noninvasively detect and monitor tRCC with high accuracy, a method that could have applicability to other genomically quiet cancers.

genomics↗

bioRxiv2024

A novel combination of CDK4/6 and PI3K inhibitors exhibits highly synergistic activity and translational potential in Ewing sarcoma.

Ewing sarcoma is a highly aggressive solid malignancy affecting children and young adults. Ewing sarcoma is driven primarily by EWSR1::FLI1, a fusion oncoprotein that has been notoriously difficult to target with traditional pharmacologic agents. There are numerous examples of preclinical promising combinations of small molecules that are never tested in pediatric clinical trials because agents fail to reach the market due to limited efficacy for common adult cancers. Moreover, the effectiveness of single-agent therapies for cancer treatment is often limited. To address these limitations, we selected 28 compounds that were largely FDA approved or in late stages of clinical development and known to regulate important pathways in Ewing sarcoma. We performed a drug screen in Ewing sarcoma cell lines with 180 combinations of tyrosine kinase inhibitors, cell cycle inhibitors, and conventional chemotherapy. The results of the screen revealed that a PI3K inhibitor, copanlisib, combined with a CDK4/6 inhibitor, ribociclib, exhibited strong synergistic anti-Ewing sarcoma activity. Using proteomic methods such as a reverse-phase protein array and western immunoblotting, we demonstrated that this combination induced a downregulation of the PI3K/AKT pathway as well as proteins involved in cell cycle regulation. We further confirmed these in vitro data using bulk RNA-sequencing. To evaluate the phenotypic effect of the PI3K/CDK4/6 inhibition in Ewing sarcoma lines, we performed apoptosis and cell cycle analyses using flow cytometry and demonstrated that ribociclib primarily induced a G0/G1 arrest with minimal effect on Ewing cell viability but significantly enhanced the apoptotic effect of copanlisib treatment. In a xenograft model of Ewing sarcoma, we demonstrated that the combination therapy significantly prolonged survival compared to treatment with either vehicle or single-agent therapy alone. Our findings identify a new candidate therapy combination for Ewing sarcoma using FDA-approved drugs and provide a resource of additional potential synergistic combinations for future validation. Statement of translational relevanceTreatment of patients with newly diagnosed Ewing sarcoma involves intensive multi- agent chemotherapy, radiation, and surgery, often leading to long-term toxicities. Children with relapsed or metastatic disease experience poor outcomes with five-year overall survival rates of only 15 to 30 percent. Therefore, new therapeutic approaches are urgently needed. Our drug screen revealed several promising combinations with synergistic anti-Ewing sarcoma activity including the PI3K inhibitor copanlisib with the CDK4/6 inhibitor ribociclib. This combination also significantly improved survival in a mouse xenograft model of Ewing sarcoma compared to treatment with vehicle or either drug alone. Pre-clinical validation of a combination therapy composed of two FDA- approved drugs nominates this combination for early phase trials for patients with with relapsed or refractory Ewing sarcoma, a group of patients greatly in need of new therapeutic opportunities. The data generated by our drug screen may also be used as a resource to identify other promising combinations for future validation as Ewing sarcoma therapies.

cancer biology↗

bioRxiv2024

Rare germline structural variants increase risk for pediatric solid tumors

AO_SCPLOWBSTRACTC_SCPLOWPediatric solid tumors are rare malignancies that represent a leading cause of death by disease among children in developed countries. The early age-of-onset of these tumors suggests that germline genetic factors are involved, yet conventional germline testing for short coding variants in established predisposition genes only identifies pathogenic events in 10-15% of patients. Here, we examined the role of germline structural variants (SVs)--an underexplored form of germline variation--in pediatric extracranial solid tumors using germline genome sequencing of 1,766 affected children, their 943 unaffected relatives, and 6,665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and a four-fold increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we revealed burdens of ultra-rare SVs that cause loss-of-function of highly expressed, mutationally intolerant, neurodevelopmental genes, as well as noncoding SVs predicted to disrupt three-dimensional chromatin domains in neural crest-derived tissues. Collectively, our results implicate rare germline SVs as a predisposing factor to pediatric solid tumors that may guide future studies and clinical practice.

genomics↗

bioRxiv2018

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. Through direct-to-patient outreach, we developed genomically faithful patient-derived models of RMC. Using whole genome sequencing, we identified intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele, confirming that SMARCB1 loss occurs in RMC. Biochemical and functional characterization of these RMC models revealed that RMC depends on the loss of SMARCB1 for survival and functionally resemble other cancers that harbor loss of SMARCB1, such as malignant rhabdoid tumors or atypical teratoid rhabdoid tumors. We performed RNAi and CRISPR-Cas9 loss of function genetic screens and a small-molecule screen and identified UBE2C as an essential gene in SMARCB1 deficient cancers. We found that the ubiquitin-proteasome pathway was essential for the survival of SMARCB1 deficient cancers in vitro and in vivo. Genetic or pharmacologic inhibition of this pathway leads to G2/M arrest due to constitutive accumulation of cyclin B1. These observations identify a synthetic lethal relationship that may serve as a therapeutic approach for patients with SMARCB1 deficient cancers.

cancer biology↗