Advancing prognostic understanding in hepatocellular carcinoma through the integration of genomic instability and lncRNA signatures: GILncSig model.

The recently published study by Duan et al introduces a promising method that combines genomic instability and long non-coding RNAs to improve the prognostic evaluation of hepatocellular carcinoma (HCC), a deadly cancer associated with considerable morbidity and mortality. This editorial aims to analyze the methodology, key findings, and broader implications of the study within the fields of gastroenterology and oncological surgery, highlighting the shift towards precision medicine in the management of HCC.

The role of the hepatitis B virus genome and its integration in the hepatocellular carcinoma.

The integration of Hepatitis B Virus (HBV) is now known to be closely associated with the occurrence of liver cancer and can impact the functionality of liver cells through multiple dimensions. However, despite the detailed understanding of the characteristics of HBV integration and the mechanisms involved, the subsequent effects on cellular function are still poorly understood in current research. This study first systematically discusses the relationship between HBV integration and the occurrence of liver cancer, and then analyzes the status of the viral genome produced by HBV replication, highlighting the close relationship and structure between double-stranded linear (DSL)-HBV DNA and the occurrence of viral integration. The integration of DSL-HBV DNA leads to a certain preference for HBV integration itself. Additionally, exploration of HBV integration hotspots reveals obvious hotspot areas of HBV integration on the human genome. Virus integration in these hotspot areas is often associated with the occurrence and development of liver cancer, and it has been determined that HBV integration can promote the occurrence of cancer by inducing genome instability and other aspects. Furthermore, a comprehensive study of viral integration explored the mechanisms of viral integration and the internal integration mode, discovering that HBV integration may form extrachromosomal DNA (ecDNA), which exists outside the chromosome and can integrate into the chromosome under certain conditions. The prospect of HBV integration as a biomarker was also probed, with the expectation that combining HBV integration research with CRISPR technology will vigorously promote the progress of HBV integration research in the future. In summary, exploring the characteristics and mechanisms in HBV integration holds significant importance for an in-depth comprehension of viral integration.

Cytome analysis (micronuclei and nuclear anomalies) in bioindication of environmental pollution in animals with nuclear erythrocytes.

Assessment of cytogenetic homeostasis of indicator animals is of great importance in ecological monitoring. The simplest method of its study is micronucleus analysis. Animals with nuclear erythrocytes are often used as indicator animals. In addition to the micronuclei usually recorded, a wide range of cytological nuclear and cellular abnormalities (cytomic analysis) is encountered when assessing the spontaneous level and under the influence of anthropogenic factors. Spontaneous frequency of cytogenetic disorders in 36 species of fish, amphibians, reptiles and birds was studied. Ecological monitoring of territories of Kazakhstan with different types of pollution (radiation, petrochemical, pesticide, heavy metals, due to rocket and space activities) was carried out with the help of separate species of animals. The results of the study include comparative descriptions, schematics and microphotographs clearly demonstrating a wide range of cytological anomalies of nuclear erythrocytes of animals of different classes. The greatest spectrum of nuclear anomalies in the studied animals was registered at petrochemical and pesticide contamination of territories. Depending on the tasks and climatic-geographical conditions, all investigated species can be used as bioindicators. Testudo horsfieldii is an exception for desert regions due to high spontaneous micronuclei level in this species. A review of the names of the main nuclear anomalies is carried out and variants of its ordering are proposed.

The impact of opioids on the hallmarks of ageing.

Opioids rank among the most hazardous substances of abuse, leading to opioid use disorders (which greatly diminish life quality) and contributing to the highest drug-related mortality rates. Nonetheless, both the therapeutic and recreational use of opioids is escalating globally. Interestingly, chronic opioid users often exhibit signs consistent with accelerated ageing, suggesting that they likely interfere with well-characterized ageing mechanisms (e.g., telomere shortening, epigenetic changes, mitochondrial dysfunction, cellular senescence). Here, we review the most recent advances regarding the impact of opioids on well-characterized hallmarks of ageing, to ascertain a potential association between opioid use and accelerated ageing. Our findings indicate that there is accumulating evidence supporting a close association between the use of opioids and the early onset of some ageing hallmarks, namely mitochondrial dysfunction, genomic instability, or telomere shortening. However, there is still limited data available regarding how opioids specifically impact other ageing hallmarks, like nutrient sensing, cellular senescence, or loss of proteostasis. Taking into consideration the high prevalence of opioid use, strengthening the understanding of the mechanisms underlying opioids' impact on ageing assumes utmost relevance, both in terms of improving risk assessment, as well as to help researchers and clinicians prevent or mitigate these effects in clinical settings.

A comprehensive review of PRAME and BAP1 in melanoma: Genomic instability and immunotherapy targets.

In a thorough review of the literature, the complex roles of PRAME (preferentially expressed Antigen of Melanoma) and BAP1 (BRCA1-associated protein 1) have been investigated in uveal melanoma (UM) and cutaneous melanoma. High PRAME expression in UM is associated with poor outcomes and correlated with extraocular extension and chromosome 8q alterations. BAP1 mutations in the UM indicate genomic instability and a poor prognosis. Combining PRAME and BAP1 immunohistochemical staining facilitates effective risk stratification. Mechanistically, both genes are associated with genomic instability, making them promising targets for cancer immunotherapy. Hypomethylation of PRAME, specifically in its promoter regions, is critical for UM progression and contributes to epigenetic reprogramming. Additionally, miR-211 regulation is crucial in melanoma and has therapeutic potential. The way PRAME changes signaling pathways provides clues about the cause of cancer due to genomic instability related to modifications in DNA repair. Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in cells expressing PRAME could lead to potential therapeutic applications. Pathway enrichment analysis underscores the significance of PRAME and BAP1 in melanoma pathogenesis.

Clinical application value of long non-coding RNAs signatures of genomic instability in predicting prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) presents challenges due to its high recurrence and metastasis rates and poor prognosis. While current clinical diagnostic and prognostic indicators exist, their accuracy remains imperfect due to their biological complexity. Therefore, there is a quest to identify improved biomarkers for HCC diagnosis and prognosis. By combining long non-coding RNA (lncRNA) expression and somatic mutations, Duan et al identified five representative lncRNAs from 88 lncRNAs related to genomic instability (GI), forming a GI-derived lncRNA signature (LncSig). This signature outperforms previously reported LncSig and TP53 mutations in predicting HCC prognosis. In this editorial, we comprehensively evaluate the clinical application value of such prognostic evaluation model based on sequencing technology in terms of cost, time, and practicability. Additionally, we provide an overview of various prognostic models for HCC, aiding in a comprehensive understanding of research progress in prognostic evaluation methods.

Liver Transplantation for Nijmegen Breakage Syndrome With Hepatic Malignancy and Hepatopulmonary Syndrome After Bone Marrow Transplantation: A Case Report.

BACKGROUND: Nijmegen breakage syndrome (NBS) is an autosomal recessive DNA repair disorder that manifests through increased genomic instability, malignancy, and cellular and humoral immunodeficiencies. The prognosis for NBS patients is poor due to their increased susceptibility to fatal infections and lymphoproliferative malignancies. Currently, there is no specific treatment for NBS, though allogeneic hematopoietic stem cell transplantation (HSCT) has been performed and documented as case series to demonstrate the utility of transplantation. METHODS: A 14-year-old girl with NBS and haploidentical HSCT from her older brother due to recurrent lung infection was referred for liver transplantation (LT) due to liver cirrhosis, hepatopulmonary syndrome (HPS), and suspicion of liver malignancy. It was decided to perform LT using the living donor who had previously donated for HSCT. RESULTS: Living donor left lobe LT was successfully performed from her brother. The patient experienced no complications in the early postoperative period and was discharged on the seventh postoperative day. Pathological examination of extracted liver has shown "intermediate cell carcinoma" in two foci. After 1 year LT, the patient has had an uneventful course in terms of LT complications and infection, with minimal immunosuppression. CONCLUSIONS: NBS patients have an increased prevalence of malignancies, including primary hepatic malignancy, but most are managed medically or with limited resections. Transplantation in these patients can be curative for hepatic malignancy with a favorable safety profile.

Genomic instability in congenital lung malformations in children.

PURPOSE: To study the biological relationship between congenital lung malformations (CLMs) and malignancy. METHODS: Biopsies of 12 CPAMs, 6 intralobar sequestrations and 2 extralobar sequestrations were analyzed through whole-genome sequencing. Blood samples from 10 patients were used to confirm or exclude somatic mosaicism. Putative somatic Single Nucleotide Variants (SNVs) were called for each malformed sample with a Panel of Normals built with control DNA samples extracted from blood. The variants were subsequently confirmed by Sanger sequencing and searched, whenever possible, in the blood samples of patients. RESULTS: All CLMs but one presented a signature of genomic instability by means of multiple clusters of cells with gene mutations. Seven tumor transformation-related SNVs were detected in 6/20 congenital lung malformations. Four very rare in the general population SNVs were found in a region previously linked to lung cancer in 5p15.33, upstream of TERT oncogene. Furthermore, we identified missense genetic variants, whose tumorigenic role is well known, in the RET, FANCA and MET genes. CONCLUSIONS: Genomic instability in 95% of CLMs and genetic variants linked to tumor development in 30% of them, regardless of histopathology, are predisposing factors to malignancy, that combined with exposure to carcinogens, might trigger the development of malignancy and explain the association between CLMs and lung cancer.

Significance of P53-Binding Protein 1 as a Novel Molecular Histological Marker for Hypopharyngeal Squamous Neoplasms.

The DNA damage response protein p53-binding protein 1 (53BP1) accumulates and forms foci at double-strand DNA breaks, indicating the extent of DNA instability. However, the potential role of 53BP1 as a molecular biomarker for hypopharyngeal squamous cell carcinoma (HPSCC) diagnosis remains unknown. Here, we evaluated the potential of immunofluorescence-based analysis of 53BP1 expression to differentiate the histology of hypopharyngeal neoplasms. A total of 125 lesions from 39 surgically or endoscopically resected specimens from patients with HPSCC was histologically evaluated. 53BP1 expression in the nucleus was examined using immunofluorescence. The number of 53BP1 nuclear foci increased with the progression from non-tumorous to low-grade dysplasia, high-grade dysplasia, and squamous cell carcinoma. Unstable 53BP1 expression served as an independent factor for distinguishing lesions that required intervention. Colocalization of 53BP1 foci in proliferating cells, as assessed by Ki67, was increased in tumors ≥ 1000 µm in depth compared to those <1000 µm in depth at the tumor surface. Hence, the expression patterns of nuclear 53BP1 foci were associated with the progression of hypopharyngeal neoplasms. These findings suggest that 53BP1 could serve as an ancillary marker to support histological diagnosis and predict the factors that influence prognosis in patients with HPSCC.

Epigenetic alterations in bioaccumulators of cadmium: Lessons from mammalian kidneys and plants.

Faced with unpredictable changes in global weather patterns, release and redistribution of metals through land erosion and water movements add to the increasing use of metals in industrial activities causing high levels of environmental pollution and concern to the health of all living organisms. Cadmium is released into the environment by smelting and mining, entering the food chain via contaminated soils, water, and phosphate fertilizers. Bioaccumulation of cadmium in plants represents the first major step into the human food chain and contributes to toxicity of several organs, especially the kidneys, where biomagnification of cadmium occurs over decades of exposure. Even in small amounts, cadmium brings about alterations at the molecular and cellular levels in eukaryotes through mutagenicity, molecular mimicry at metal binding sites and oxidative stress. The epigenome dictates expression of a gene's output through a number of regulatory steps involving chromatin remodeling, nucleosome unwinding, DNA accessibility, or nucleic acid modifications that ultimately impact the transcriptional and translational machinery. Several epigenetic enzymes exhibit zinc-dependence as zinc metalloenzymes and zinc finger proteins thus making them susceptible to deregulation through displacement by cadmium. In this review, we summarize the literature on cadmium-induced epigenetic mechanisms in mammalian kidneys and plants, compare similarities in the epigenetic defense between these bioaccumulators, and explore how future studies could advance our understanding of the cadmium-induced stress response and disruption to biological health.

Molecular Alterations Associated with Histologically Overt Stromal Response in Patients with Prostate Cancer.

Prostate cancer has substantial heterogeneity in clinical outcomes and therapeutic responses, posing challenges in predicting disease progression and tailoring treatment strategies. Recent studies have highlighted the potential prognostic value of evaluating the tumor microenvironment, including the presence of a histologically overt stromal response (HOST-response) characterized by peri-glandular stromal changes and architectural distortions. This retrospective study examined patient records from The Cancer Genome Atlas database to identify genomic alterations associated with the HOST-response in prostate cancer. Among 348 patients who underwent radical prostatectomy, 160 (45.98%) were identified as having a HOST-response. A gene expression analysis revealed 1263 genes with significantly higher expression in patients with a HOST-response. A protein-protein interaction network analysis identified seven hub genes (KIF2C, CENPA, CDC20, UBE2C, ESPL1, KIF23, and PLK1) highly interconnected in the network. A functional enrichment analysis revealed alterations in the cell division, cytoskeletal organization, cytokinesis, and interleukin-16 signaling pathways in patients with a HOST-response, suggesting dysregulated proliferation and inflammation. The distinct molecular signature associated with the HOST-response provides insights into the tumor-stroma interactions driving adverse outcomes and potential targets for tailored therapeutic interventions in this subset of patients with prostate cancer.

Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a "genomically unstable" cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients' well-being.

The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance.

Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCI-FANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 endonuclease subsequently induces large-scale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extrachromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers cancer genome evolution through chromothripsis.

DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma.

Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.

Arid1a Loss Enhances Disease Progression in a Murine Model of Osteosarcoma.

Osteosarcoma is an aggressive bone malignancy, molecularly characterized by acquired genome complexity and frequent loss of TP53 and RB1. Obtaining a molecular understanding of the initiating mutations of osteosarcomagenesis has been challenged by the difficulty of parsing between passenger and driver mutations in genes. Here, a forward genetic screen in a genetic mouse model of osteosarcomagenesis initiated by Trp53 and Rb1 conditional loss in pre-osteoblasts identified that Arid1a loss contributes to OS progression. Arid1a is a member of the canonical BAF (SWI/SNF) complex and a known tumor suppressor gene in other cancers. We hypothesized that the loss of Arid1a increases the rate of tumor progression and metastasis. Phenotypic evaluation upon in vitro and in vivo deletion of Arid1a validated this hypothesis. Gene expression and pathway analysis revealed a correlation between Arid1a loss and genomic instability, and the subsequent dysregulation of genes involved in DNA DSB or SSB repair pathways. The most significant of these transcriptional changes was a concomitant decrease in DCLRE1C. Our findings suggest that Arid1a plays a role in genomic instability in aggressive osteosarcoma and a better understanding of this correlation can help with clinical prognoses and personalized patient care.

Tau-mediated coupling between Pol III synthesis and DnaB helicase unwinding helps maintain genomic stability.

The τ-subunit of the clamp loader complex physically interacts with both the DnaB helicase and the polymerase III (Pol III) core α-subunit through domains IV and V, respectively. This interaction is proposed to help maintain rapid and efficient DNA synthesis rates with high genomic fidelity and plasticity, facilitating enzymatic coupling within the replisome. To test this hypothesis, CRISPR-Cas9 editing was used to create site-directed genomic mutations within the dnaX gene at the C terminus of τ predicted to interact with the α-subunit of Pol III. Perturbation of the α-τ binding interaction in vivo resulted in cellular and genomic stress markers that included reduced growth rates, fitness, and viabilities. Specifically, dnaX:mut strains showed increased cell filamentation, mutagenesis frequencies, and activated SOS. In situ fluorescence flow cytometry and microscopy quantified large increases in the amount of ssDNA gaps present. Removal of the C terminus of τ (I618X) still maintained its interactions with DnaB and stimulated unwinding but lost its interaction with Pol III, resulting in significantly reduced rolling circle DNA synthesis. Intriguingly, dnaX:L635P/D636G had the largest induction of SOS, high mutagenesis, and the most prominent ssDNA gaps, which can be explained by an impaired ability to regulate the unwinding speed of DnaB resulting in a faster rate of in vitro rolling circle DNA replication, inducing replisome decoupling. Therefore, τ-stimulated DnaB unwinding and physical coupling with Pol III acts to enforce replisome plasticity to maintain an efficient rate of synthesis and prevent genomic instability.

Introducing the Role of Genotoxicity in Neurodegenerative Diseases and Neuropsychiatric Disorders.

Decades of research have identified genetic and environmental factors involved in age-related neurodegenerative diseases and, to a lesser extent, neuropsychiatric disorders. Genomic instability, i.e., the loss of genome integrity, is a common feature among both neurodegenerative (mayo-trophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) and psychiatric (schizophrenia, autism, bipolar depression) disorders. Genomic instability is associated with the accumulation of persistent DNA damage and the activation of DNA damage response (DDR) pathways, as well as pathologic neuronal cell loss or senescence. Typically, DDR signaling ensures that genomic and proteomic homeostasis are maintained in both dividing cells, including neural progenitors, and post-mitotic neurons. However, dysregulation of these protective responses, in part due to aging or environmental insults, contributes to the progressive development of neurodegenerative and/or psychiatric disorders. In this Special Issue, we introduce and highlight the overlap between neurodegenerative diseases and neuropsychiatric disorders, as well as the emerging clinical, genomic, and molecular evidence for the contributions of DNA damage and aberrant DNA repair. Our goal is to illuminate the importance of this subject to uncover possible treatment and prevention strategies for relevant devastating brain diseases.

Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency.

Accurate detection of homologous recombination deficiency (HRD) in cancer patients is paramount in clinical applications, as HRD confers sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. With the advances in genome sequencing technology, mutational profiling on a genome-wide scale has become readily accessible, and our knowledge of the genomic consequences of HRD has been greatly expanded and refined. Here, we review the recent advances in HRD detection methods. We examine the copy number and structural alterations that often accompany the genome instability that results from HRD, describe the advantages of mutational signature-based methods that do not rely on specific gene mutations, and review some of the existing algorithms used for HRD detection. We also discuss the choice of sequencing platforms (panel, exome, or whole-genome) and catalog the HRD detection assays used in key PARP inhibitor trials.

Progerin Can Induce DNA Damage in the Absence of Global Changes in Replication or Cell Proliferation.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging, and individuals with HGPS seldom live beyond their mid-teens. The syndrome is commonly caused by a point mutation in the LMNA gene which codes for lamin A and its splice variant lamin C, components of the nuclear lamina. The mutation causing HGPS leads to production of a truncated, farnesylated form of lamin A referred to as "progerin." Progerin is also expressed at low levels in healthy individuals and appears to play a role in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs) and alterations in the nature of DSB repair. The source of DSBs in HGPS is often attributed to stalling and subsequent collapse of replication forks in conjunction with faulty recruitment of repair factors to damage sites. In this work, we used a model system involving immortalized human cell lines to investigate progerin-induced genomic damage. Using an immunofluorescence approach to visualize phosphorylated histone H2AX foci which mark sites of genomic damage, we report that cells engineered to express progerin displayed a significant elevation of endogenous damage in the absence of any change in the cell cycle profile or doubling time of cells. Genomic damage was enhanced and persistent in progerin-expressing cells treated with hydroxyurea. Overexpression of wild-type lamin A did not elicit the outcomes associated with progerin expression. Our results show that DNA damage caused by progerin can occur independently from global changes in replication or cell proliferation.

Genomic Insights Into High-Grade Infarct-Associated Bone Sarcomas.

Sarcomas rarely develop in bones previously compromised by infarcts. These infarct-associated sarcomas often present as undifferentiated pleomorphic sarcomas (UPS), and their genetic characteristics are poorly understood. High-grade UPS of bone are typically treated with a combination of surgery and chemotherapy, similar to osteosarcoma. We conducted a detailed clinicopathologic and genomic analysis of 6 cases of intraosseous sarcomas arising from histologically and radiographically confirmed bone infarcts. We analyzed 523 genes for sequence-level mutations using next-generation sequencing with the TruSight Oncology 500 panel and utilized whole-genome single nucleotide polymorphism Microarray (OncoScan CNV) to detect copy number alterations and loss of heterozygosity (LOH). Genomic instability was assessed through homologous recombination deficiency (HRD) metrics, incorporating LOH, telomeric allelic imbalance, and large-scale state transitions. Fluorescence in situ hybridization and immunohistochemistry validated the findings. The cohort included 3 men and 3 women, with a median age of 70 years, and tumors located in the femur and tibia. Five of the 6 patients developed distant metastases. Treatment involved surgery and chemotherapy or immune checkpoint inhibitors. Genomic analysis revealed significant complexity and high HRD scores, ranging from 32 to 57 (with a cutoff of 32). Chromosome 12 alterations, including segmental amplification or chromothripsis, were observed in 4 cases. Notably, MDM2 amplification, confirmed by fluorescence in situ hybridization, was detected in 2 cases. Homozygous deletion of CDKN2A/B was observed in all six cases. Tumor mutational burden levels ranged from 2.4 to 7.9 mutations per megabase. Notable pathogenic mutations included H3-3A mutations (p.G35R and p.G35W), and mutations in HRAS, DNMT3A, NF2, PIK3CA, POLE, and TP53, each in one case. These results suggest that high-grade infarct-associated sarcomas of bone, whereas sharing high levels of structural variations with osteosarcoma, may exhibit potentially less frequent TP53 mutations and more common CDKN2A/B deletions. This points to the possibility that the mutation spectrum and disrupted pathways could be distinct from conventional osteosarcoma.