Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution.

Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas.

A deep learning framework deploying segment anything to detect pan-cancer mitotic figures from haematoxylin and eosin-stained slides.

Mitotic activity is an important feature for grading several cancer types. However, counting mitotic figures (cells in division) is a time-consuming and laborious task prone to inter-observer variation. Inaccurate recognition of MFs can lead to incorrect grading and hence potential suboptimal treatment.

Introduction and impact of routine whole genome sequencing in the diagnosis and management of sarcoma.

Background: Sarcomas are diverse neoplasms with highly variable histological appearances in which diagnosis is often challenging and management options for metastatic/unresectable disease limited. Many sarcomas have distinctive molecular alterations, but the range of alterations is large, variable in type and rapidly increasing, meaning that testing by limited panels is unable to capture the broad spectrum of clinically pertinent genomic drivers required. Paired whole genome sequencing (WGS) in contrast allows comprehensive assessment of small variants, copy number and structural variants along with mutational signature analysis and germline testing.

Epigenetic age acceleration is a distinctive trait of epithelioid sarcoma with potential therapeutic implications.

Recently, DNA methylation clocks have been proven to be precise age predictors, and the application of these clocks in cancer tissue has revealed a global age acceleration in a majority of cancer subtypes when compared to normal tissue from the same individual. The polycomb repressor complex 2 plays a pivotal role in the aging process, and its targets have been shown to be enriched in CpG sites that gain methylation with age. This complex is further regulated by the chromatin remodeling complex SWItch/Sucrose Non-Fermentable and its core subunit, notably the tumor suppressor gene SMARCB1, which under physiological conditions inhibits the activity of the polycomb repressor complex 2.