Pan-cancer atlas of somatic core and linker histone mutations DOI Creative Commons
Erin R. Bonner, Adam Dawood, Heather Gordish‐Dressman

et al.

npj Genomic Medicine, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 28, 2023

Abstract Recent genomic data points to a growing role for somatic mutations altering core histone and linker histone-encoding genes in cancer. However, the prevalence clinical biological implications of gene malignant tumors remain incompletely defined. To address these knowledge gaps, we analyzed 88 across 12,743 from pediatric, adolescent young adult (AYA), cancer patients. We established pan-cancer mutation atlas contextualized by patient age, survival outcome, tumor location. Overall, 11% harbored mutations, with highest rates observed among chondrosarcoma (67%), pediatric high-grade glioma (pHGG, >60%), lymphoma (>30%). Previously unreported were discovered pHGG other brain tumors, extending spectrum alterations associated cancers. Histone status predicted outcome entities including adrenocortical carcinoma. Recurrent hotspots defined shown converge on evolutionarily conserved functional residues. Moreover, studied 1700 cell lines validate seen primary derived histone-associated drug response profiles, revealing candidate drugs targeting mutant cells. This study presents first-of-its-kind both AYA, cancers, providing framework which specific cancers may be redefined context chromatin alterations.

Language: Английский

Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population DOI Creative Commons
C. Benedikt Westphalen, Matthew Krebs,

C. Le Tourneau

et al.

npj Precision Oncology, Journal Year: 2021, Volume and Issue: 5(1)

Published: July 20, 2021

Abstract Neurotrophic tropomyosin receptor kinase ( NTRK) gene fusions are rare oncogenic drivers in solid tumours. This study aimed to interrogate a large real-world database of comprehensive genomic profiling data describe the landscape and prevalence NTRK fusions. fusion-positive tumours were identified from FoundationCORE ® >295,000 cancer patients. We investigated concomitant fusions, predicted patient ancestry compared cohort with entrectinib clinical trial cohorts (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). Overall tumour was 0.30% among 45 cancers 88 unique fusion partner pairs, which 66% previously unreported. Across all cases, 0.28% 1.34% patients aged ≥18 <18 years, respectively; highest <5 years (2.28%). The observed salivary gland (2.62%). Presence did not correlate other clinically actionable biomarkers; there no co-occurrence known breast, or colorectal (CRC). However, CRC, fusion-positivity associated spontaneous microsatellite instability (MSI); this MSI CRC subset, mutual exclusivity BRAF mutations observed. types had similar frequencies trials. varied greatly by age, type histology. Interrogating datasets drives better understanding characteristics very molecular subgroups allows identification patterns unreported partners evident smaller datasets.

Language: Английский

Citations

147
Unified rhombic lip origins of group 3 and group 4 medulloblastoma DOI
Kyle Smith,

Laure Bihannic,

Brian Gudenas

et al.

Nature, Journal Year: 2022, Volume and Issue: 609(7929), P. 1012 - 1020

Published: Sept. 21, 2022

Language: Английский

Citations

96
Accelerating the understanding of cancer biology through the lens of genomics DOI Creative Commons
Dongfang Wang, Baolin Liu, Zemin Zhang

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1755 - 1771

Published: April 1, 2023

Language: Английский

Citations

45
Beyond genetics: driving cancer with the tumour microenvironment behind the wheel DOI
Shaopeng Yuan, Jorge Almagro, Elaine Fuchs

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(4), P. 274 - 286

Published: Feb. 12, 2024

Language: Английский

Citations

45
Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers DOI Creative Commons
Arlet Acanda de la Rocha, Noah Berlow, Maggie Fader

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 990 - 1000

Published: April 1, 2024

Children with rare, relapsed or refractory cancers often face limited treatment options, and few predictive biomarkers are available that can enable personalized recommendations. The implementation of functional precision medicine (FPM), which combines genomic profiling drug sensitivity testing (DST) patient-derived tumor cells, has potential to identify options when standard-of-care is exhausted. goal this prospective observational study was generate FPM data for pediatric patients cancer. primary objective determine the feasibility returning FPM-based recommendations in real time board (FPMTB) within a clinically actionable timeframe (<4 weeks). secondary assess clinical outcomes from enrolled study. Twenty-five solid hematological were enrolled; 21 underwent DST 20 also completed profiling. Median turnaround times genomics 10 days 27 days, respectively. Treatment made 19 (76%), whom 14 received therapeutic interventions. Six subsequent FPM-guided treatments. Among these patients, five (83%) experienced greater than 1.3-fold improvement progression-free survival associated their therapy relative previous therapy, demonstrated significant increase response rate compared those eight non-guided patients. findings our proof-of-principle illustrate positively impact care adolescent warrant further validation large studies. ClinicalTrials.gov registration: NCT03860376 .

Language: Английский

Citations

22
The Role of Chronic Inflammation in Pediatric Cancer DOI Open Access

Christine Mella,

Panogiotis Tsarouhas,

Maximillian Brockwell

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(1), P. 154 - 154

Published: Jan. 6, 2025

Inflammation plays a crucial role in wound healing and the host immune response following pathogenic invasion. However, unresolved chronic inflammation can result tissue fibrosis genetic alterations that contribute to pathogenesis of human diseases such as cancer. Recent scientific advancements exploring underlying mechanisms malignant cellular transformations cancer progression have exposed significant disparities between pediatric adult-onset cancers. For instance, cancers tend lower mutational burdens arise actively developing tissues, where cell-cycle dysregulation leads gene, chromosomal, fusion gene development not seen counterparts. As such, findings adult cannot be directly applied cancers, unique mutations inherent etiologies remain poorly understood. Here, we review processes chromosomal instability, tumor microenvironment, tumorigenesis transformation explore current therapeutic interventions maintain and/or restore inflammatory homeostasis.

Language: Английский

Citations

3
Combined low-pass whole genome and targeted sequencing in liquid biopsies for pediatric solid tumors DOI Creative Commons
Eirini Christodoulou, Venkata Yellapantula, Katrina O’Halloran

et al.

npj Precision Oncology, Journal Year: 2023, Volume and Issue: 7(1)

Published: Feb. 20, 2023

Abstract We designed a liquid biopsy (LB) platform employing low-pass whole genome sequencing (LP-WGS) and targeted of cell-free (cf) DNA from plasma to detect genome-wide copy number alterations (CNAs) gene fusions in pediatric solid tumors. A total 143 samples were analyzed 19 controls 73 patients, including 44 bone or soft-tissue sarcomas 12 renal, 10 germ cell, five hepatic, two thyroid cfDNA was isolated collected at diagnosis, during after therapy, and/or relapse. Twenty-six 37 (70%) patients enrolled diagnosis without prior therapy (radiation, surgery, chemotherapy) had circulating tumor (ctDNA), based on the detection CNAs LP-WGS, 18 27 (67%) with localized disease eight (80%) metastatic disease. None detectable somatic CNAs. There high concordance identified by LP-WGS detected chromosomal microarray analysis matching Mutations our next-generation (NGS) panel, OncoKids®, also ctDNA 14 26 samples. Finally, we developed hybridization-based capture panel target EWSR1 FOXO1 Ewing sarcoma alveolar rhabdomyosarcoma (ARMS), respectively. Fusions ARMS. Combined, these data demonstrate clinical applicability LB evaluate variety

Language: Английский

Citations

36
Diagnostic classification of childhood cancer using multiscale transcriptomics DOI Creative Commons
Federico Comitani, Joshua O. Nash, Sarah Cohen‐Gogo

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(3), P. 656 - 666

Published: March 1, 2023

The causes of pediatric cancers' distinctiveness compared to adult-onset tumors the same type are not completely clear and fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach derive molecular definitions for most childhood cancers. Applying method 13,313 transcriptomes, constructed a cancer atlas explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due common lineages, drivers or stemness profiles. Some established divided into subgroups that predicted outcome better than current diagnostic approaches. These account inter-tumoral intra-tumoral heterogeneity have potential enabling reproducible, quantifiable diagnostics. As whole, had more transcriptional diversity adult tumors, maintaining greater expression flexibility. To apply these insights, designed ensemble convolutional neural network classifier. We show tool was able match clarify diagnosis 85% in prospective cohort. If further validated, framework could be extended all types.

Language: Английский

Citations

23
Benefits for children with suspected cancer from routine whole-genome sequencing DOI Creative Commons
Angus Hodder, Sarah M. Leiter, Jonathan Kennedy

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(7), P. 1905 - 1912

Published: July 1, 2024

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits children with cancer and alter treatment in high-risk patient groups. It remains unknown whether offering WGS every child suspected can change management. We collected variant calls clinical diagnostic information from 281 (282 tumors) across two English units (n = 152 a hematology center, n 130 solid tumor center) where had become routine test. Our key finding was that variants uniquely attributable changed the management ~7% (20 out of 282) cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, 108 instances for 83 (29%) cases. Furthermore, faithfully reproduced test 738) revealed several previously genomic features childhood tumors. show be delivered as part care by delivering unexpected insights. experience portrays clinically impactful assay practice, opportunities consolidation delivery molecularly informed care.

Language: Английский

Citations

12
Approval of DFMO for high-risk neuroblastoma patients demonstrates a step of success to target MYC pathway DOI
Jun Yang

British Journal of Cancer, Journal Year: 2024, Volume and Issue: 130(4), P. 513 - 516

Published: Feb. 5, 2024

Language: Английский

Citations

10