Chromoanagenesis in Osteosarcoma

Abstract

Chromoanagenesis is a catastrophic genomic phenomenon involving sudden, extensive rearrangements within one or a few cell cycles. In osteosarcoma, the most prevalent malignant bone tumor in children and adolescents, these events dramatically alter the genomic landscape, frequently disrupting key tumor suppressor genes like TP53 and RB1, amplifying oncogene expression, and propelling tumor progression and evolution. This review elucidates how key chromoanagenic mechanisms, such as chromothripsis and chromoanasynthesis, arise from replication stress and impaired DNA repair pathways, ultimately contributing to genomic instability in osteosarcoma. Chromothripsis features prominently in osteosarcoma, occurring in up to 62% of tumor regions and driving intratumoral heterogeneity through persistent genomic crises. Next-generation sequencing, optical genome mapping, and emerging technologies like single-cell sequencing empower researchers to detect and characterize these complex structural variants, demonstrating how a single catastrophic event can profoundly influence osteosarcoma progression over time. While targeted therapies for osteosarcoma have proven elusive, innovative strategies harnessing comprehensive genomic profiling and patient-derived preclinical models hold promise for uncovering tumor-specific vulnerabilities tied to chromoanagenesis. Ultimately, unraveling how these rapid, large-scale rearrangements fuel osteosarcoma's aggressive nature will not only refine disease classification and prognosis but also pave the way for novel therapeutic approaches to enhance patient outcomes.

Keywords: chromoanagenesis; chromoanasynthesis; chromothripsis; copy number variant; gene mutation; osteosarcoma; structural variant.

Figure 1

Conventional osteosarcoma is a high-grade bone-producing sarcoma which generally grows in an aggressive permeative fashion as seen here, (A) infiltrating through native cancellous bone trabeculae. The identification of mineralized osteoid is necessary for the diagnosis; mineralized osteoid may vary from wispy and lacelike (B) to coarse (C), abundant, and extensively sclerotic (A,D). (A) has a magnification of 40×, (B) has a magnification of 100×, (C) has a mag-nification of 200×, and (D) has a magnification of 100×.

Figure 2

Chromosomes, genes, and variants in osteosarcoma with chromoanagenesis. (A) Genes in the chromosome (left side) and chromosomes (right side) involved in chromoanagenesis. (B) Genes with SVs. (C) Genes with CNVs. (D) Genes with SNVs.

Figure 2

Chromosomes, genes, and variants in osteosarcoma with chromoanagenesis. (A) Genes in the chromosome (left side) and chromosomes (right side) involved in chromoanagenesis. (B) Genes with SVs. (C) Genes with CNVs. (D) Genes with SNVs.

Figure 3

The role of chromoanagenesis in osteosarcoma. This conceptual model illustrates how chromoanagenesis initiates tumorigenesis, fuels clonal evolution and heterogeneity, underlies mechanisms of therapeutic resistance, and indicates potential therapeutic interventions. The figure was created using BioRender (http://biorender.com/, accessed on 22 May 2025).

Figure 4

Mechanisms and differences among three types of chromoanagenesis. Chromoanagenesis comprises chromothripsis, chromoplexy, and chromoanasynthesis in terms of mechanisms and key features. Chromothripsis involves chromosomal shattering and reassembly via NHEJ. Chromoplexy leads to chain-like rearrangements across multiple chromosomes. Chromoanasynthesis results from replication errors, causing localized copy number gains. The table highlights their distinct characteristics. The figure was created using BioRender (http://biorender.com/, accessed on 17 February 2025).

Figure 5

Technologies for detecting chromoanagenesis and their key advantages and limitations. Three categories of technologies for detecting chromoanagenesis are illustrated: cytogenetic methods (karyotyping, FISH, OGM, Hi-C), array-based and sequencing approaches (CGH/SNP arrays, short-read and long-read genome sequencing), and single-cell sequencing coupled with multi-omics profiling. Each method has distinct strengths, such as resolution, genome-wide coverage, or detection of SVs, as well as limitations, including cost, complexity, and detection biases. The table summarizes their key advantages and limitations. The tumors shown on the human skeleton indicate common sites of osteosarcoma occurrence, with larger tumor sizes being associated with a higher incidence. The figure was created using BioRender (http://biorender.com/, accessed on 8 March 2025).