Search Results (24)

Background: Sarcomas are rare, aggressive malignancies with limited therapeutic options in advanced stages. This is the first real-world study in the MENA region evaluating the clinical utility of Next-Generation Sequencing (NGS) in guiding sarcoma treatment and improving outcomes. Methods: We retrospectively reviewed sarcoma patients who underwent NGS at a major referral center (2021–2024), comparing clinical and molecular outcomes between those who received NGS-based treatment adjustments (NBTA) and those who did not. Results: Seventy-eight patients were included (60% male; median age 44 years). Soft tissue sarcomas accounted for 70.5% of cases (n = 55), while bone sarcomas represented 29.5% (n = 23). Prior to NGS, 64.1% of patients had received a median of one line of systemic therapy. NGS was performed late in the disease course in 73% of cases. At least one mutation was detected in 87% (median 3 mutations). Targetable alterations were identified in 33% at the time of testing, rising to 42% with updated genomic knowledge and therapeutic advances. Overall, 20.5% received NBTA. Among non-NBTA patients, 67% had no actionable targets, 17% had no detectable mutations, and 16% were ineligible due to cost, limited access, or clinical deterioration. Tumor Mutational Burden was low in 79%, intermediate in 19%, and high in 2%, and all tumors were microsatellite stable. Patients receiving NBTA had a longer median Progression-Free Survival (9 vs. 2 months; p = 0.023). Median Overall Survival was longer in the NBTA group (74 vs. 48 months), though not statistically significant (p = 0.207). Genomic alterations were subtype-specific: EWSR1 rearrangements (Ewing and Desmoplastic small round cell tumors), CDK4 and MDM2 amplifications (Liposarcoma and Osteosarcoma), TP53 and RB1 mutations (Leiomyosarcoma), CDKN2A/B deletions (Undifferentiated Pleomorphic Sarcoma and Chondrosarcoma), and SS18 rearrangements (Synovial Sarcoma). Conclusions: Genomics-guided therapy in sarcoma is feasible and impactful. Expanding timely access to molecular profiling is essential for advancing precision oncology in the MENA region. Full article

Over the past several decades, rapid advances in molecular genomics have transformed our understanding of thyroid malignancies and are increasingly integrated into international clinical guidelines. Mutational profiles and epigenetic events are now recognized not only as diagnostic and prognostic tools but also as predictors of therapeutic response. Papillary, follicular, oncocytic, medullary, and anaplastic thyroid carcinomas harbor distinct early driver mutations, such as BRAFV600E, RAS, and fusion events (RET, NTRK, and ALK), that cooperate with secondary alterations (TERT promoter, TP53, PIK3CA, and CDKN2A/B loss) to drive dedifferentiation, metastasis, and therapeutic resistance. Insights from The Cancer Genome Atlas (TCGA) and transcriptomic scoring systems (e.g., BRAF–RAS score) now link genotype to tumor morphology, metastatic tropism, and radioactive iodine refractoriness. These molecular insights have been incorporated into updated risk stratification frameworks, preoperative surgical planning, and treatment algorithms, informing the selection of kinase inhibitors, redifferentiation strategies, and enrollment in genotype-directed clinical trials for radioiodine-refractory disease. This review synthesizes recent evidence connecting genomic alterations to clinical behavior and highlights their translation into evolving approaches for thyroid cancer management. Full article

Background/Objectives: Astrocytoma, IDH-mutant, CNS WHO grade 3, is a diffuse glioma with poor prognosis, molecularly defined by IDH mutations and frequently co-occurring TP53 and ATRX alterations. This study aimed to delineate the genomic landscape and identify clinically relevant molecular features of astrocytoma, IDH-mutant, CNS WHO grade 3 using this resource. Methods: Patients in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) database were selected based on histological diagnosis of “anaplastic astrocytoma”, confirmed IDH1/2 mutation, and exclusion of CDKN2A/B homozygous deletions. We analyzed frequencies of somatic mutations, copy number alterations (CNAs), structural variants (SVs), assessed co-occurrence/exclusivity patterns, and explored associations with available demographic and limited survival data. Results: The most common somatic mutations were in IDH1 (98.0%), TP53 (94.8%), and ATRX (55.2%). The observed ATRX mutation frequency was lower than some historical reports (e.g., ~86%). Other recurrent alterations included phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (6.9%), Notch receptor 1 (NOTCH1) (6.9%), and platelet-derived growth factor receptor alpha (PDGFRA) (mutations 4.3%; CNAs also observed). Conclusions: This study provides a comprehensive genomic characterization of astrocytoma, IDH-mutant, CNS WHO grade 3 using the AACR GENIE database, confirming core mutational signatures while also highlighting potential variations in alteration frequencies, such as for ATRX. The findings establish a valuable real-world genomic benchmark for this tumor type, while promoting the need for continued data integration with robust clinical outcomes to identify actionable prognostic and therapeutic targets. Full article

Optical genome mapping (OGM) is a novel, high-resolution technology for genome-wide detection of structural variants, offering clear advantages over conventional cytogenetics in hematologic malignancies. We applied OGM to a large cohort of patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDSs), and B-cell acute lymphoblastic leukemia (B-ALL) to evaluate its clinical utility. In AML and MDS, it revealed high-risk alterations such as deletions in 5q31–5q32 and 7q22, and cryptic fusions like NUP98::NSD1 that were missed by karyotyping or FISH. It also identified chromoanagenesis, a catastrophic chromosomal event linked to poor prognosis and often undetectable by standard methods. In B-ALL, OGM uncovered clinically relevant deletions in CDKN2A/B, PAX5, and IKZF1, as well as high-risk ploidy changes like hypodiploidy and hyperdiploidy, all important for risk assessment and frequently underdetected. OGM not only refines diagnosis and improves risk stratification but can also uncover cryptic and complex genomic abnormalities. Our findings support its integration into routine diagnostics to enhance classification, guide treatment decisions, and improve patient outcomes. Full article

Background/Objectives: This study evaluates intratumoral susceptibility signals (ITSS) as imaging markers for glioma grade prediction and their association with molecular and histopathologic features, in the context of the fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5). Methods: We retrospectively analyzed patients with adult diffuse gliomas who underwent pretreatment magnetic resonance imaging. ITSS were semiquantitatively graded by two radiologists: grade 0 (no signal), grade 1 (1–5), grade 2 (6–10), and grade 3 (≥11). Relative cerebral blood volume (rCBV) and tumor volume were also obtained. Histopathologic features included tumor grade, Ki-67, mitotic count, necrosis, microvascular proliferation, and molecular alterations (isocitrate dehydrogenase [IDH], 1p/19q, cyclin-dependent kinase inhibitors 2A and 2B [CDKN2A/B], and p53). Regression models predicted tumor grade (low: 1–2, high: 3–4) using ITSS, tumor volume, and rCBV. ROC curves and diagnostic performance metrics were analyzed. Results: 99 patients were included. ITSS grading correlated with rCBV, tumor volume, mitotic count, Ki-67, and tumor grade (p < 0.001). ITSS grades 0–1 were associated with oligodendrogliomas and astrocytomas (p < 0.001), IDH mutations (p < 0.001), and 1p/19q co-deletions (p = 0.01). ITSS grades 2–3 were linked to glioblastomas (p < 0.001), necrosis (p < 0.001), microvascular proliferation (p < 0.001), and CDKN2A/B homozygous deletions (p = 0.02). Models combining ITSS with rCBV and volume showed AUC of 0.94 and 0.96 (p < 0.001), outperforming univariate models. Conclusions: Semiquantitative ITSS grading correlates with key histopathologic and molecular glioma features. Combined with perfusion and volumetric parameters, ITSS enhance non-invasive glioma grading, in alignment with WHO CNS5. Full article

Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling. Methods: A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations were also common among the TERT promoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified among PBRM1, BRCA2, and KMT2D mutations. CDKN2A/B deletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults. Conclusions: This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions. Full article

Gliomas are a heterogeneous group of brain tumors, among which the most aggressive subtype is glioblastoma, accounting for 60% of cases in adults. Available systemic treatment options are few and ineffective, so new approaches to therapies for glioblastoma are in high demand. In total, 131 patients with diffuse glioma were studied. Paired tumor–normal samples were sequenced on the Illumina platform; the panel included 812 genes associated with cancer development. Molecular profiles in clinically distinct groups were investigated. In low-grade glioma (LGG) patients (n = 18), the most common mutations were IDH1/2 (78%), ATRX (33%), TP53 (33%), PIK3CA (17%), and co-deletion 1p/19q (22%). In high-grade glioma (HGG) patients (n = 113), more frequently affected genes were CDKN2A/B (33%), TERTp (71%), PTEN (60%), TP53 (27%), and EGFR (40%). The independent predictors of better prognosis were tumor grade and IDH1/2 mutations. In IDH—wildtype glioblastoma patients, a history of other precedent cancer was associated with worse overall survival (OS), while re-operation and bevacizumab therapy increased OS. Also, among genetic alterations, TERTp mutation and PTEN deletion were markers of poor prognosis. Nine patients received molecular targeted therapy, and the results were evaluated. The search for molecular changes associated with tumor growth and progression is important for diagnosis and choice of therapy. Full article

The World Health Organization Classification of Tumors of the Central Nervous System recently incorporated histological features, immunophenotypes, and molecular characteristics to improve the accuracy of glioblastoma (GBM) diagnosis. FGFR3::TACC3 (F3T3) fusion has been identified as an oncogenic driver in IDH-wildtype GBMs. Recent studies have demonstrated the potential of using FGFR inhibitors in clinical trials and TACC3-targeting agents in preclinical models for GBM treatment. However, there is limited information on the clinicopathological and genetic features of IDH-wildtype GBMs with F3T3 fusion. The aim of this study was to comprehensively investigate the clinical manifestations, histological features, and mutational profiles of F3T3-positive GBMs. Between September 2017 and February 2023, 25 consecutive cases (5.0%) of F3T3-positive GBM were extracted from 504 cases of IDH-wildtype GBM. Clinicopathological information and targeted sequencing results obtained from 25 primary and 4 recurrent F3T3-positive GBMs were evaluated and compared with those from F3T3-negative GBMs. The provisional grades determined by histology only were distributed as follows: 4 (26/29; 89.7%), 3 (2/29; 6.9%), and 2 (1/29; 3.4%). Grade 2–3 tumors were ultimately diagnosed as grade 4 GBMs based on the identification of the TERT promoter mutation and the combined gain of chromosome 7 and loss of chromosome 10 (7+/10−). F3T3-positive GBMs predominantly affected women (2.6 females per male). The mean age of patients with an F3T3-positive GBM at initial diagnosis was 62 years. F3T3-positive GBMs occurred more frequently in the cortical locations compared to F3T3-negative GBMs. Imaging studies revealed that more than one-third (12/29; 41.4%) of F3T3-positive GBMs displayed a circumscribed tumor border. Seven of the seventeen patients (41.2%) whose follow-up periods exceeded 20 months died of the disease. Histologically, F3T3-positive GBMs more frequently showed curvilinear capillary proliferation, palisading nuclei, and calcification compared to F3T3-negative GBMs. Molecularly, the most common alterations observed in F3T3-positive GBMs were TERT promoter mutations and 7+/10−, whereas amplifications of EGFR, PDGFRA, and KIT were not detected at all. Other genetic alterations included CDKN2A/B deletion, PTEN mutation, TP53 mutation, CDK4 amplification, and MDM2 amplification. Our observations suggest that F3T3-positive GBM is a distinct molecular subgroup of the IDH-wildtype GBM. Both clinicians and pathologists should consider this rare entity in the differential diagnosis of diffuse astrocytic glioma to make an accurate diagnosis and to ensure appropriate therapeutic management. Full article

The landscape of chromosomal aberrations in the tumor cells of the patients with B-ALL is diverse and can influence the outcome of the disease. Molecular karyotyping at the onset of the disease using chromosomal microarray (CMA) is advisable to identify additional molecular factors associated with the prognosis of the disease. Molecular karyotyping data for 36 patients with Ph-negative B-ALL who received therapy according to the ALL-2016 protocol are presented. We analyzed copy number alterations and their prognostic significance for CDKN2A/B, DMRTA, DOCK8, TP53, SMARCA2, PAX5, XPA, FOXE1, HEMGN, USP45, RUNX1, NF1, IGF2BP1, ERG, TMPRSS2, CRLF2, FGFR3, FLNB, IKZF1, RUNX2, ARID1B, CIP2A, PIK3CA, ATM, RB1, BIRC3, MYC, IKZF3, ETV6, ZNF384, PTPRJ, CCL20, PAX3, MTCH2, TCF3, IKZF2, BTG1, BTG2, RAG1, RAG2, ELK3, SH2B3, EP300, MAP2K2, EBI3, MEF2D, MEF2C, CEBPA, and TBLXR1 genes, choosing t(4;11) and t(7;14) as reference events. Of the 36 patients, only 5 (13.8%) had a normal molecular karyotype, and 31 (86.2%) were found to have various molecular karyotype abnormalities—104 deletions, 90 duplications or amplifications, 29 cases of cnLOH and 7 biallelic/homozygous deletions. We found that 11q22-23 duplication involving the BIRC3, ATM and MLL genes was the most adverse prognostic event in the study cohort. Full article

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations—heterozygous deletions (HeD), point mutations, and promoter methylation—is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker. Full article

Meningiomas are common tumors of the central nervous system. The grading system established by the World Health Organization (WHO) has recently included pTERT mutations and CDKN2A/B homozygous deletions as criteria for grade 3, owing to their association with increased recurrence risk. However, these alterations identify only a portion of meningiomas that are devoid of histopathological malignancy and are prone to recurrence. Over the last few years, the integration of epigenetic, genetic, transcriptomic, and proteomic profiling has led to the identification of three main groups of meningiomas with distinct clinical outcomes and peculiar genetic features. Meningiomas in the first group have the best prognosis, are distinguished by the lack of NF2 alterations and chromosomal instability, and may be responsive to cytotoxic drugs. Meningiomas in the second group have an intermediate prognosis and are characterized by NF2 alterations, mild chromosomal instability, and enrichment in immune cells. Meningiomas in the third group had the worst prognosis, displayed NF2 alterations coupled with high chromosomal instability, and were resistant to cytotoxic treatment. Classification into these three groups predicts the recurrence risk of meningiomas more accurately than WHO grading and could be applicable in routine practice, owing to the possibility of distinguishing the different groups by specific immunostaining. Full article

Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial–mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as COL5A2, ITGAV, SERPINH1, CALD1, SPARC, and ACTA2 were associated with upregulation of TGF-β signaling, hedgehog signaling, and IL-2-STAT5 signaling and downregulation of the IFN-α and IFN-γ response. Immune checkpoints such as CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1), and TIGIT were upregulated, while LAG3, LGALS9, and VTCN1 were downregulated with the expression of MESO EMT genes. CD160, KIR2DL1, and KIR2DL3 were also broadly downregulated with the expression of MESO EMT genes. In conclusion, we observed that the expression of a panel of MESO EMT genes was associated with hypermethylation of epigenetic genes and loss of expression of CDKN2A and CDKN2B. Expression of MESO EMT genes was associated with downregulation of the type I and type II IFN response, loss of cytotoxicity and NK cell activity, and upregulation of specific immune checkpoints, as well as upregulation of the TGF-β1/TGFBR1 pathway. Full article

Despite their rarity, thymic epithelial tumors (TETs) have attracted much interest over the years, leading to an impressive number of histological and staging classifications. At present, TETs are divided by the WHO classification into four main subtypes: type A, type AB, and type B thymomas (subdivided into B1, B2, and B3), and thymic carcinomas, going from the more indolent to the most aggressive ones. Among many debated staging proposals, the TNM and the Masaoka–Koga staging systems have been widely accepted and used in routine practice. The four-tiered histological classification is symmetrically mirrored by the molecular subgrouping of TETs, which identifies an A-like and an AB-like cluster, with frequent GTF2I and HRAS mutations; an intermediate B-like cluster, with a T-cell signaling profile; and a carcinoma-like cluster comprising thymic carcinomas with frequent CDKN2A and TP53 alterations and a high tumor molecular burden. Molecular investigations have opened the way to tailored therapies, such as tyrosine kinase inhibitors targeting KIT, mTOR, and VEGFR, and immune-checkpoints that have been adopted as second-line systemic treatments. In this review, we discuss the crucial events that led to the current understanding of TETs, while disclosing the next steps in this intriguing field. Full article

Sarcomas are rare malignant mesenchymal neoplasms, and the knowledge of tumor biology and genomics is scarce. Chemotherapy is the standard of care in advanced disease, with poor outcomes. Identifying actionable genomic alterations may offer effective salvage therapeutic options when previous lines have failed. Here, we report a retrospective cohort study of sarcoma patients followed at our center and submitted to comprehensive genomic profiling between January 2020 and June 2021. Thirty patients were included, most (96.7%) with reportable genomic alterations. The most common alterations were linked to cell cycle regulation (TP53, CDKN2A/B, and RB1 deletions and CDK4, MDM2, and MYC amplifications). Most patients (96.7%) had microsatellite stability and low tumor mutational burden (≤10 muts/megabase (Mb); median 2 Muts/Mb). Two-thirds of patients had actionable mutations for targeted treatments, including five cases with alterations amenable to targeted therapies with clinical benefit within the patient’s tumor type, ten cases with targetable alterations with clinical benefit in other tumor types, and five cases with alterations amenable to targeting with drugs under investigation in a clinical trial setting. A significant proportion of cases in this study had actionable genomic alterations with available targeted drugs. Next-generation sequencing is a feasible option for identifying molecular drivers that can provide therapeutic options for individual patients. Molecular Tumor Boards should be implemented in the clinical practice to discuss genomic findings and inform clinically relevant targeted therapies. Full article

Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1, CDKN2A/B, and NF2 are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with genomic alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B genomic alterations consistently contributed to an adverse clinical outcome. Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies. Full article