Optical Genome Mapping for Comprehensive Cytogenetic Analysis of Soft-Tissue and Bone Tumors for Diagnostic Purposes.

Soft-tissue and bone tumors represent a heterogeneous group of tumors encompassing more than 100 histologic subtypes today. Identifying genetic aberrations increasingly is important in these tumors for accurate diagnosis. Although gene mutations typically are detected by second-generation sequencing, the identification of structural variants (SVs) and copy number alterations (CNAs) remains challenging and requires various cytogenetic techniques including karyotyping, fluorescence in situ hybridization, and arrays, each with important limitations. Optical Genome Mapping (OGM), a non-sequencing-based technique for high-resolution detection of SVs and CNAs, was applied in a retrospective series of diagnostic soft-tissue and bone tumor samples. Sample preparation was successful in 38 of 53 cases, with the highest success rate in nonadipocytic soft-tissue tumors (24 of 27 cases; 89%). In 32 of 35 cases carrying a diagnostic SV or CNA, OGM identified the aberration (91%), including a POU2AF3::EWSR1 fusion in a round cell sarcoma and a translocation t(1;5)(p22;p15) in a myxoinflammatory fibroblastic sarcoma. Interestingly, OGM shed light on the genomic complexity underlying the various aberrations. In five samples, OGM showed that chains of rearrangements generated the diagnostic fusion, three of which involved chromoplexy. In addition, in nine samples, chromothripsis was causal to the formation of giant marker/ring/double-minute chromosomes. Finally, compared with standard-of-care cytogenetics, OGM revealed additional aberrations, requiring further investigation of their potential clinical relevance.

Endothelial cell autophagy in homeostasis and cancer.

Autophagy, the major lysosomal pathway for the degradation and recycling of cytoplasmic materials, is increasingly recognized as a major player in endothelial cell (EC) biology and vascular pathology. Particularly in solid tumors, tumor microenvironmental stress such as hypoxia, nutrient deprivation, inflammatory mediators, and metabolic aberrations stimulates autophagy in tumor-associated blood vessels. Increased autophagy in ECs may serve as a mechanism to alleviate stress and restrict exacerbated inflammatory responses. However, increased autophagy in tumor-associated ECs can re-model metabolic pathways and affect the trafficking and surface availability of key mediators and regulators of the interplay between EC and immune cells. In line with this, heightened EC autophagy is involved in pathological angiogenesis, inflammatory, and immune responses. Here, we review major cellular and molecular mechanisms regulated by autophagy in ECs under physiological conditions and discuss recent evidence implicating EC autophagy in tumor angiogenesis and immunosurveillance.