Biology subjects

Hehir-Kwa, J. Y.

Publications and source records attributed to Hehir-Kwa, J. Y..

6 recordsLinked to original sources

bioRxiv2023

Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors

BackgroundIn pediatric cancer, structural variants (SVs) and copy number alterations can contribute to cancer initiation and progression, and hence aid diagnosis and treatment stratification. The few studies into complex rearrangements have found associations with tumor aggressiveness or poor outcome. Yet, their prevalence and biological relevance across pediatric solid tumors remains unknown. ResultsIn a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy and chromothripsis across five pediatric solid cancer types: neuroblastoma, Ewing sarcoma, Wilms tumor, hepatoblastoma and rhabdomyosarcoma. Complex SVs were identified in 56 tumors (47%) and different classes occurred across multiple cancer types. Recurrently mutated regions tend to be cancer-type specific and overlap with cancer genes, suggesting that selection contributes to shaping the SV landscape. In total, we identified potentially pathogenic complex SVs in 42 tumors that affect cancer driver genes or result in unfavorable chromosomal alterations. Half of which were known drivers, e.g. MYCN amplifications due to ecDNA and EWSR1::FLI1 fusions due to chromoplexy. Recurrent novel candidate complex events include chromoplexy in WT1 in Wilms tumors, focal chromothripsis with 1p loss in hepatoblastomas and complex MDM2 amplifications in rhabdomyosarcomas. ConclusionsComplex SVs are prevalent and pathogenic in pediatric solid tumors. They represent a type of genomic variation which currently remains unexplored. Moreover, carrying complex SVs seems to be associated with adverse clinical events. Our study highlights the potential for complex SVs to be incorporated in risk stratification or exploited for targeted treatments.

cancer biology↗

bioRxiv2022

Molecular characterization reveals subclasses of 1q gain in intermediate-risk Wilms tumors

Chromosomal alterations have recurrently been identified in Wilms tumors (WTs) and some are associated with poor prognosis. Gain of 1q (1q+) is of special interest given its high prevalence and is currently actively studied for its prognostic value. However, the underlying mutational mechanisms and functional effects remain unknown. For 30 primary WTs, we integrated somatic SNVs, CNs and SVs with expression data and distinguished four clusters characterized by affected biological processes: muscle differentiation, immune system, kidney development and proliferation. We identified 1q+ in eight tumors that differ in mutational mechanisms, subsequent rearrangements and genomic contexts. 1q+ tumors were present in all four expression clusters and individual tumors overexpress different genes on 1q. Through integrating CNs, SVs and gene expression, we identified subgroups of 1q+ tumors reflecting differences in the functional effect of 1q gain, indicating that expression data is likely needed for further risk stratification of 1q+ WTs.

cancer biology↗

bioRxiv2022

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here we describe the generation of a collection of pediatric RMS tumor organoid (tumoroid) models comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within four to eight weeks, indicating the feasibility of personalized drug screening. Molecular, genetic and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to six months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.

cancer biology↗

bioRxiv2021

Systematic discovery of gene fusions in pediatric cancer by integrating RNA-seq and WGS

BackgroundGene fusions are important cancer drivers in pediatric cancer and their accurate detection is essential for diagnosis and treatment. Clinical decision-making requires high confidence and precision of detection. Recent developments show RNA sequencing (RNA-seq) is promising for genome-wide detection of fusion products, but hindered by many false positives that require extensive manual curation and impede discovery of pathogenic fusions. ResultsWe developed Fusion-sq to detect tumor-specific gene fusions by integrating and "fusing" evidence from RNA-seq and whole genome sequencing (WGS) using intron-exon gene structure. In a pediatric pan-cancer cohort of 130 patients, we identified 165 high confidence tumor-specific gene fusions and their underlying structural variants (SVs). This includes all clinically relevant fusions known to be present in this cohort (30 patients). Fusion-sq distinguishes healthy-occurring from tumor-specific fusions, and resolves fusions in amplified regions and copy number unstable genomes. A high gene fusion burden is associated with copy number instability. We identified 27 potentially pathogenic fusions involving oncogenes or tumor-suppressor genes characterised by underlying SVs or expression changes indicative of activating or disruptive effects. ConclusionsOur results indicate how clinically relevant and potentially pathogenic gene fusions can be identified and their functional effects investigated by combining WGS and RNA-seq. Integrating RNA fusion predictions with underlying SVs advances fusion detection beyond extensive manual filtering. Taken together, we developed a method for identifying candidate fusions that is suitable for precision oncology applications. Our method provides multi-omics evidence for assessing the pathogenicity of tumor-specific fusions for future clinical decision making.

genomics↗

bioRxiv2021

Epigenetic regulator genes direct lineage switching in MLL-AF4 leukaemia

The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, multipotent progenitors or committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes indicating that the execution and maintenance of lymphoid lineage differentiation is impaired. We show that this subversion is recurrently associated with the dysregulation of repressive chromatin modifiers, notably the nucleosome remodelling and deacetylation complex, NuRD. In addition to mutations, we show differential expression or alternative splicing of NuRD members and other genes is able to reprogram the B lymphoid into a myeloid gene regulatory network. Lineage switching in MLL-AF4 leukaemia is therefore driven and maintained by defunct epigenetic regulation. Statement of SignificanceWe demonstrate diverse cellular origins of lineage switched relapse within MLL-AF4 pro-B acute leukaemia. Irrespective of the developmental origin of relapse, dysregulation of NuRD and/or other epigenetic machinery underpins fundamental lineage reprogramming with profound implications for the increasing use of epitope directed therapies in this high-risk leukaemia.

cancer biology↗

bioRxiv2020

PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors.

Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms. Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.

cancer biology↗