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PubMed2026

Tumor Mutational Concordance and Recurrence Timing in Hepatocellular Carcinoma.

INTRODUCTION: In hepatocellular carcinoma (HCC), intrahepatic recurrence includes true recurrence from clonal relapse and multicentric recurrence from de novo tumorigenesis. Recurrence timing is used to distinguish these types; however, its accuracy remains unclear. This study aimed to classify recurrent tumors based on somatic mutational concordance and assess the validity of recurrence timing. METHODS: Whole-exome sequencing was performed on paired primary and recurrent HCC tumors from 49 patients enrolled in a prospective institutional omics project. Tumors with ≥ 10 shared somatic mutations were classified as true recurrence. Clinicopathological features, recurrence timing, driver mutation patterns, and survival outcomes were compared between recurrence types. Mutational concordance was quantified using shared variant counts and the Jaccard similarity index. RESULTS: Of the 49 patients, 22 (44.9%) showed true recurrence and 27 (55.1%) had multicentric recurrence. Multicentric recurrence tumors harbored no shared variants or only a single shared variant with the primary tumor. True recurrence was associated with significantly higher concordance in histological differentiation and Edmondson-Steiner grading and greater retention of CTNNB1, TP53, ARID1A, and KEAP1 mutations. The number of shared variants (median: 115 vs. 0, and p < 0.001) and the Jaccard index (median: 0.44 vs. 0.00 and p < 0.001) were significantly higher in the true recurrence group. Recurrence timing was inconsistently correlated with mutational concordance, although a 3-year cutoff yielded significant separation. CONCLUSION: Recurrence timing alone insufficiently reflects clonal relationships. Genomic profiling offers a reliable framework for distinguishing between recurrence types and guiding HCC management.

clonal relapse↗

PubMed2026

Beyond Morphology: Reframing Lymph-Node Metastasis Prediction Through Clonal Ecology-Decades-Long Genomic Instability and Polyclonal-to-Monoclonal Transitions as the Missing Dimension in Cancer.

Recent whole-genome, lineage-tracing, single-cell, and spatial studies have reshaped our understanding of tumor evolution, revealing that cancers can arise from polyclonal populations, undergo decades-long genomic instability before clinical detection, and progress through dynamic changes in subclonal composition, cellular state, and ecological organization. These findings challenge the assumption underlying morphology-based prediction models that metastatic risk can be inferred from static histological features alone. Here, we revisit lymph-node metastasis prediction in colorectal cancer through clonal ecology, integrating computational pathology with evolutionary oncology. Drawing on the subclonal switchboard model proposed in 2012 and subsequent artificial intelligence (AI)-enabled approaches for tracking dominant and dormant subclones, we synthesize evidence that metastatic potential reflects clonal ancestry, evolutionary timing, spatial niche architecture, cellular plasticity, intercellular interactions, dormancy, and treatment-driven shifts in subclonal fitness. We define five complementary methodological pillars for operationalizing clonal ecology: single-cell transcriptomics for resolving rare subclones, evolutionary trajectories, and adaptive cell states; lineage tracing and phylogenetics for reconstructing clonal ancestry and divergence; spatial transcriptomics and genomics for mapping subclonal geography and tumor-stromal-immune interactions; longitudinal liquid biopsy surveillance for monitoring residual disease, clonal turnover, and emerging resistance; and AI-enabled multimodal integration for connecting histopathology, genomics, spatial biology, and longitudinal data into predictive ecological-state models. Multiple-instance learning and pathology foundation models provide scalable computational foundations for evolution-aware prediction. Translationally, dormant subclones represent actionable reservoirs of recurrence. A longitudinal clinical and experimental study of KMT2A-rearranged acute myeloid leukemia further supports central predictions of the subclonal switchboard framework by demonstrating treatment-associated shifts in subclonal dominance, persistence of cryptic adaptive programs, and ecological rewiring during resistance and relapse. We propose clonal ecology as a measurable dimension for extending morphology-driven prediction toward integrative models that anticipate evolutionary transitions, identify therapeutic windows, and proactively constrain adaptive tumor ecosystems before resistant or metastatic subclones achieve clinical dominance.

Humans↗

PubMed2022

High early death rates, treatment resistance, and short survival of Black adolescents and young adults with AML.

Survival of patients with acute myeloid leukemia (AML) is inversely associated with age, but the impact of race on outcomes of adolescent and young adult (AYA; range, 18-39 years) patients is unknown. We compared survival of 89 non-Hispanic Black and 566 non-Hispanic White AYA patients with AML treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols. Samples of 327 patients (50 Black and 277 White) were analyzed via targeted sequencing. Integrated genomic profiling was performed on select longitudinal samples. Black patients had worse outcomes, especially those aged 18 to 29 years, who had a higher early death rate (16% vs 3%; P=.002), lower complete remission rate (66% vs 83%; P=.01), and decreased overall survival (OS; 5-year rates: 22% vs 51%; P<.001) compared with White patients. Survival disparities persisted across cytogenetic groups: Black patients aged 18 to 29 years with non-core-binding factor (CBF)-AML had worse OS than White patients (5-year rates: 12% vs 44%; P<.001), including patients with cytogenetically normal AML (13% vs 50%; P<.003). Genetic features differed, including lower frequencies of normal karyotypes and NPM1 and biallelic CEBPA mutations, and higher frequencies of CBF rearrangements and ASXL1, BCOR, and KRAS mutations in Black patients. Integrated genomic analysis identified both known and novel somatic variants, and relative clonal stability at relapse. Reduced response rates to induction chemotherapy and leukemic clone persistence suggest a need for different treatment intensities and/or modalities in Black AYA patients with AML. Higher early death rates suggest a delay in diagnosis and treatment, calling for systematic changes to patient care.

Adolescent↗

PubMed2026

Mutational Landscape and Clonal Dynamics in AML Undergoing PTCy Hematopoietic Cell Transplantation.

To improve risk stratification, we performed targeted NGS at diagnosis in 191 patients with AML undergoing myeloablative allogeneic HCT with PTCy-based prophylaxis. We also investigated clonal evolution using paired diagnostic and relapse samples from 39 individuals. A total of 610 mutations were detected in 184 patients (96%), most commonly in FLT3 (26%), DNMT3A (25%), RUNX1 (24%), and NPM1 (19%). Sixteen unique fusion genes were identified in 35 patients, with KMT2A (43%) and core binding factor rearrangements (23%) being the most frequent. TP53 and WT1 mutations were strongly associated with adverse outcomes, whereas NPM1 retained favorable significance. RUNX1 co-mutations with SF3B1 or NRAS were associated with inferior survival. In an exploratory allelic analysis, multi-hit TP53 alterations, but not single-hit mutations, were associated with distinctly poorer OS, EFS, and relapse risk. Relapse involved mutational shifts in ∼70% of cases, with significant enrichment of WT1 and more modest increases in TP53, KRAS, ASXL1, NF1, and MECOM, while DNMT3A, TET2, and ASXL1 persisted stably. Neither acute nor chronic graft-versus-host disease was associated with molecular remodeling at relapse. Incorporating TP53 and WT1 into risk models, recognizing context-dependent effects of DNMT3A and RUNX1, and applying longitudinal genomic monitoring may help guide personalized strategies to prevent relapse. Extended abstract BACKGROUND Relapse remains the leading cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML), yet the genetic mechanisms underlying post-transplant relapse remain poorly understood, particularly in the era of post-transplant cyclophosphamide (PTCy). Characterizing the mutational landscape at diagnosis and the clonal evolution leading to relapse may improve post-transplant risk stratification and identify opportunities for personalized surveillance and intervention. OBJECTIVES To characterize the diagnostic mutational landscape, evaluate its prognostic significance, and investigate clonal evolution from diagnosis to relapse in AML patients undergoing myeloablative HCT with PTCy-based graft-versus-host disease prophylaxis. STUDY DESIGN We performed targeted next-generation sequencing (NGS) at diagnosis in 191 consecutive AML patients undergoing myeloablative allogeneic HCT with PTCy-based prophylaxis. Paired diagnostic and relapse samples were available for 39 patients to evaluate clonal evolution. RESULTS A total of 610 mutations were detected in 184 patients (96%), most commonly in FLT3 (26%), DNMT3A (25%), RUNX1 (24%), and NPM1 (19%). Sixteen unique fusion genes were identified in 35 patients, with KMT2A (43%) and core binding factor rearrangements (23%) being the most frequent. TP53 and WT1 mutations were strongly associated with adverse outcomes, whereas NPM1 retained favorable significance. RUNX1 co-mutations with SF3B1 or NRAS were associated with inferior survival. In an exploratory allelic analysis, multi-hit TP53 alterations, but not single-hit mutations, were associated with distinctly poorer OS, EFS, and relapse risk. Relapse involved mutational shifts in ∼70% of cases, with significant enrichment of WT1 and more modest increases in TP53, KRAS, ASXL1, NF1, and MECOM, while DNMT3A, TET2, and ASXL1 persisted stably. Neither acute nor chronic graft-versus-host disease was associated with molecular remodeling at relapse. CONCLUSIONS This study provides a comprehensive characterization of the mutational landscape and clonal evolution of AML undergoing contemporary PTCy-based allogeneic HCT. TP53 and WT1 identify patients at particularly high risk of post-transplant relapse, whereas NPM1 retains favorable prognostic significance. The frequent acquisition of new genetic lesions at relapse underscores the dynamic nature of post-transplant clonal evolution and supports longitudinal molecular monitoring together with genomically informed post-transplant surveillance and relapse-prevention strategies.

Clonal Dynamics↗

PubMed2026

Genetic Mutation and Epigenetic Silencing Drive Antigen-Negative Relapse in CD7 CAR T-Treated T-cell Lymphoid Malignancies.

UNLABELLED: CD7 is a promising target for chimeric antigen receptor (CAR) T-cell therapy in T-cell lymphoid malignancies; however, antigen loss-mediated relapse has emerged as a major challenge. In this study, we systematically analyzed the genetic and epigenetic alterations of paired specimens (pretreatment and relapsed) from 10 patients with T-cell lymphoma/leukemia receiving CD7 CAR T cells. Overall, we identified three distinct mechanisms underlying CD7 loss: first, frameshift insertion (patient 4; c.164dupG:p.R55fs) or deletion (patient 7; c.122delG:p.G41Efs*19) resulting in truncation of the CD7 transmembrane domain in two of 10 patients; second, hypermethylation of the CD7 promoter in seven of 10 patients without CD7 mutation; third, simultaneous occurrence of promoter region hypermethylation and multiple in-frame mutations with predicted functional interference in one of 10 patients (patient 2). Collectively, these findings demonstrate that both clonal heterogeneity and epigenetic plasticity drive antigen-negative relapse in T-cell lymphoid malignancies under the selective pressure of CD7 CAR T-cell therapy. SIGNIFICANCE: Understanding mechanisms of antigen-negative relapse is critical for developing effective CD7-targeting CAR-T therapies against T-cell lymphoid malignancies. Our study identifies both genetic truncation mutations and epigenetic silencing as contributors to CD7-negative relapse. Monitoring and preventing these events is warranted to improve treatment outcomes.

Humans↗

PubMed2025

Cytogenetic and molecular characterization of an atypical ETP-ALL case with BCL2 dependency: therapeutic implications for Venetoclax use.

BACKGROUND: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare, high-risk subtype of T-ALL characterized by distinctive immunophenotypic and genomic features. It is often associated with induction failure and frequent relapses. Despite recent advances in its molecular characterization, the prognosis remains dismal, and effective targeted therapies are limited. METHODS AND RESULTS: We report a pediatric, multi-refractory ETP-ALL case with novel cytogenetic alterations, including a 4q deletion and a t(16;18)(q24;q21) translocation. Molecular profiling revealed progressive activation of the BCL2 pathway and disruption of Th17-related immune markers. Ex vivo sensitivity assays performed at different disease stages demonstrated increasing BCL2 dependency. Based on these findings, venetoclax was administered on a compassionate-use basis, resulting in rapid hematologic recovery and a marked reduction in blast percentage. CONCLUSIONS: This case highlights the role of clonal evolution and immune deregulation in accompanying BCL2 addiction in relapsed ETP-ALL. Altogether, our findings underscore the therapeutic potential of venetoclax in refractory pediatric ETP-ALL cases with progressive BCL2 dependency.

Humans↗

PubMed2025

Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.

Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.

Leukemia, Myeloid, Acute↗

PubMed2025

Integrating multi-omics approaches in acute myeloid leukemia (AML): Advancements and clinical implications.

Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hematologic malignancy characterized by clonal proliferation of myeloid precursors. Despite significant advancements in genomic profiling and targeted therapies, patient outcomes remain suboptimal due to disease complexity, resistance mechanisms, and high relapse rates. The integration of multi-omics approaches-spanning genomics, epigenomics, transcriptomics, proteomics, and metabolomics-has revolutionized AML research, offering a comprehensive understanding of leukemogenesis, tumor heterogeneity, and therapeutic vulnerabilities. Recent studies leveraging high-throughput sequencing, mass spectrometry, and advanced computational tools have uncovered novel biomarkers, clonal evolution dynamics, and microenvironmental interactions that drive AML progression and resistance. For instance, single-cell multi-omics has revealed chemotherapy-resistant leukemic stem cell populations, while proteogenomic analyses have identified actionable targets such as MCL1 and metabolic dependencies like OXPHOS. Clinically, integrated omics platforms are refining risk stratification, minimal residual disease (MRD) monitoring, and personalized therapy selection. However, challenges such as data integration complexity, cost barriers, and ethical considerations remain. This review highlights the transformative potential of multi-omics in AML, emphasizing recent advancements in technology, biomarker discovery, and therapeutic innovation. By bridging the gap between molecular insights and clinical practice, multi-omics integration promises to redefine AML management, paving the way for precision oncology and improved patient outcomes.

Humans↗

PubMed2026

Defining and managing high-risk acute myeloid leukemia (AML) in 2026.

Acute myeloid leukemia (AML) remains a highly heterogeneous malignancy in which outcomes are particularly poor for patients classified as having high-risk disease. Traditionally, high-risk AML has been defined by adverse baseline genetic features, including complex cytogenetics, TP53 alterations, and mutations associated with secondary or therapy-related disease. However, this static, genetics-centered definition is increasingly insufficient in the modern therapeutic era. Emerging evidence supports a more dynamic and context-dependent model in which risk is shaped not only by molecular architecture but also by treatment intensity, patient fitness, measurable residual disease (MRD), and evolving resistance mechanisms. Advances in genomic profiling have refined risk stratification frameworks, including ELN 2022 for intensively treated patients and the ELN 2024 classification for those receiving less-intensive therapies. In parallel, MRD has emerged as a powerful biomarker that reclassifies patients during treatment, identifying those with persistent, therapy-resistant disease despite morphologic remission. Biologically, high-risk AML is driven by the interplay of clonal evolution, epigenetic plasticity, leukemic stem cell persistence, and protective microenvironmental and immune interactions, all of which contribute to relapse. Therapeutically, the landscape has expanded to include targeted agents, venetoclax-based combinations, and transplantation strategies, yet outcomes remain limited in key high-risk subsets, particularly TP53-mutated disease and post-venetoclax relapse. Accordingly, current strategies emphasize rational combination therapies, MRD-guided treatment adaptation, and approaches targeting both leukemic cells and their supportive niches. In 2026, high-risk AML is best understood as a dynamic, treatment-context-dependent state. Improving outcomes will require integration of precision diagnostics, biologically informed therapy, and adaptive strategies designed to anticipate and overcome resistance.

Humans↗

PubMed2026

Late acquisition of BCR::ABL1 during clonal evolution of SAMD9-associated MDS with phenotypic shift from AML to B-ALL.

We describe a unique case of SAMD9-associated myelodysplastic syndrome (MDS) with monosomy 7 that evolved over 16 years into BCR::ABL1-positive acute myeloid leukemia (AML) and subsequently manifested as B-cell acute lymphoblastic leukemia (B-ALL). Genomic analysis at AML diagnosis revealed a germline SAMD9 mutation together with somatic RUNX1 and PPM1D mutations, supporting stepwise clonal evolution, with BCR::ABL1 emerging as a late leukemogenic event. The dominant leukemic population at AML onset showed myeloid morphology and immunophenotype, whereas a minor CD19+CD10+ population was already detectable. Following venetoclax and azacitidine therapy, the dominant leukemic phenotype shifted to B-ALL while retaining BCR::ABL1 positivity. Detection of the Philadelphia chromosome in mature neutrophils at both AML onset and ALL relapse supported multilineage involvement of a multipotent BCR::ABL1-positive clone. Ponatinib achieved disease control. This case highlights late acquisition of BCR::ABL1 during SAMD9-associated clonal evolution and therapy-driven phenotypic shift within a shared Ph-positive leukemic stem-cell hierarchy.

Humans↗

PubMed2026

Measurable Residual Disease and the Unresolved Biology of Leukemic Stem Cells.

Measurable residual disease (MRD) testing has transformed the management of hematologic cancers by enabling detection of residual malignant cells after therapy. Current approaches rely on qPCR and next-generation sequencing to monitor leukemia-associated somatic mutations, while multiparameter flow cytometry identifies aberrant leukemic immunophenotypes. Although these methods provide valuable prognostic and therapeutic information, MRD negativity remains an imperfect surrogate for cure. Most MRD platforms evaluate CD45+, rapidly dividing leukemic populations and fail to detect quiescent cells that may survive cytotoxic therapies which efficiently target proliferating hematopoietic cells. Relapse frequently occurs despite deep molecular remission, suggesting persistence of rare leukemic stem cells (LSCs) that are intrinsically resistant to chemotherapy and targeted therapies. The paradox of relapse despite molecular remission could be explained by the presence of very small embryonic-like stem cells (VSELs) which are pluripotent, quiescent stem cells sitting at the top of cellular hierarchy in multiple adult tissues including bone marrow. A pluripotent VSEL divides through asymmetrical cell division to give rise to two cells of different sizes and fates, smaller cell is to self-renew while the bigger is lineage-restricted and tissue-committed progenitor which undergoes extensive epigenetic changes, divides rapidly and undergoes clonal expansion before further differentiation. Dysfunctions of VSELs initiate both solid and hematologic cancers. Based on this view, somatic mutations monitored during MRD assessment possibly represent downstream consequences of clonal expansion rather than the initiating drivers of disease persistence. Thus, exclusive monitoring of somatic mutations and CD45 + leukemic populations possibly overlook rare, small-sized, CD45- VSELs that contribute to therapeutic resistance and relapse.

Humans↗

PubMed2026

Case Report: Immune-driven clonal selection underlying lineage switch from B-Precursor acute lymphoblastic leukemia to acute myeloid leukemia following inotuzumab ozogamicin.

Lineage switch (LS), defined as a change in leukemic lineage during the disease course, is a rare but clinically significant event in acute leukemia and is typically associated with poor prognosis. Although LS has been increasingly reported following targeted immunotherapies, the clonal mechanisms underlying this phenomenon remain incompletely understood, particularly in cases without KMT2A rearrangement. We report a case of LS from B-precursor acute lymphoblastic leukemia (BCP-ALL) to acute myeloid leukemia (AML) following treatment with the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin. To elucidate the clonal architecture underlying LS, targeted next-generation sequencing was performed on bone marrow samples obtained at multiple time points throughout the disease course. Genomic analysis demonstrated that the lymphoid and myeloid disease phases shared ancestral genetic alterations but displayed distinct mutational profiles. At the time of LS, TP53 and SMC1A mutations newly emerged, whereas only a subset of mutations detected at ALL relapse was retained. These findings suggest that the AML phase most likely resulted from the selective expansion of a genetically distinct subclone derived from a common progenitor, rather than the direct transdifferentiation of the dominant ALL clone, consistent with immunotherapy-driven clonal selection. Longitudinal genomic profiling revealed stepwise clonal evolution during disease progression, supporting a model of immunotherapy-driven clonal selection leading to LS. This case provides molecular evidence suggesting that immune-targeted therapy can promote expansion of minor pre-existing subclones with alternative lineage potential within a common progenitor even in non-KMT2A-rearranged leukemia. Our findings highlight the importance of comprehensive genomic monitoring during immunotherapy to identify therapy-resistant subclones and better understand mechanisms of lineage plasticity in acute leukemia.

Humans↗

PubMed2026

Eltrombopag Added to Standard Immunosuppressive Treatment as Front-Line Therapy for Severe Aplastic Anemia: Long-Term Outcomes of the Phase-3 Randomized Superiority EBMT-SAAWP RACE Study.

The RACE study (NCT02009747) compared horse antithymocyte globulin (hATG) plus cyclosporine A (CsA) ± eltrombopag as initial immunosuppressive treatment (IST) for severe aplastic anemia. Here we report the final 2-year analysis of this prospective randomized phase III study. One hundred ninety-seven treatment-naive patients were randomized to standard IST (hATG 40 mg/kg × 4 days and CsA 5 mg/kg/day; arm A; n = 101) or standard IST + eltrombopag at the dose of 150 mg/day (arm B; n = 96) from day +14 until 6 months (or 3 months, in case of complete response). The median follow-up was 23.2 months. The 2-year cumulative incidence of complete response was significantly superior in arm B (62.4% vs. 35.3%; p < 0.001). The 2-year overall survival (OS) was 86% in arm A and 91% in arm B (p = 0.081), with hazard ratio (HR), adjusted for age and disease severity, of 0.54 (p = 0.064). The 2-year disease-free survival (DFS) was 56% vs. 37% (adjusted HR = 0.49; p < 0.001), while event-free survival (EFS) was 48% vs. 32% (p < 0.001), with adjusted HR = 0.54 (p < 0.001), both significantly superior for arm B. The cumulative incidence of relapse was comparable in the two arms, while evolution to clinical paroxysmal nocturnal hemoglobinuria was 8% in arm A and 1% in arm B (p = 0.041). The risk of clonal evolution remained negligible, with one patient in arm A and two in arm B developing karyotypic abnormalities. The initial hematological response benefit of eltrombopag added to IST as front-line treatment of AA is associated with better 2-year OS, DFS, and EFS without increased risk of secondary myeloid malignancies.

Humans↗

PubMed2026

Independent prognostic value of semaphorin-4D, interleukin-1β and complement activation in newly diagnosed multiple myeloma patients.

Multiple myeloma represents a systemic disease of the bone marrow (BM) niche, in which immune and skeletal pathways are tightly interconnected. However, the independent prognostic significance of bone and immune-related markers in newly diagnosed multiple myeloma (NDMM) remains incompletely understood. Semaphorin (Sema) 4D, activin-A, and periostin ELISA, LEGENDplex™ Human Bone Metabolism Panel and proteomic analysis for novel biomarker identification were conducted in 71 consecutive samples from NDMM patients. In 25 patients, genomic analysis was performed on sorted clonal plasma cells. NDMM patients had a median age at diagnosis of 65 years and a median follow-up of 2.5 years. Interleukin (IL)-1β and Sema4D levels predicted progression-free survival (PFS), highlighting their role in disease relapse. Proteomic profiling revealed a systemic signature associated with worse prognosis, enriched in complement activation components. Complement C5 significantly affected PFS and time to progression (TTP). IL-1β and C5 predicted PFS independently of the second revision of the International Staging System (R2-ISS) stage, and a similar trend was noted for Sema4D. Myeloma bone disease (MBD) did not significantly affect overall survival, PFS, or TTP, suggesting that contemporary treatments mitigate its impact. Genomic analyses identified variants associated with inferior PFS, including HLA-DRB5 (c.300_306delinsCGGG) and HLA-DQB1 (c.317_319delinsCGG). Sema4D and the IL-1β-complement cascade emerged as key drivers of disease progression, independent of R2-ISS stage, representing potential prognostic and therapeutic targets in NDMM.

Journal Article↗

PubMed2026

Genetic and clinical insights into the coexistence of multiple myeloma and diffuse large B cell lymphoma from a case report and systematic review with bioinformatics analysis.

BACKGROUND: Multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) are B-cell malignancies that rarely coexist in a single patient, presenting significant diagnostic and therapeutic challenges. While MM primarily involves clonal plasma cells, DLBCL is an aggressive lymphoid neoplasm. Investigating shared genetic mutations and understanding their clinical relevance in both cancers could provide novel insights into their pathogenesis and underlying molecular mechanisms, thereby informing future translational research. MATERIALS AND METHODS: A case report was conducted on a 52-year-old male who presented with abdominal pain and anemia. Imaging revealed lymphadenopathy, and biopsy confirmed high-grade DLBCL with concurrent bone marrow involvement suggestive of MM. Laboratory tests identified monoclonal IgM gammopathy, and the patient was treated with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) chemotherapy for DLBCL followed by autologous stem cell transplantation (ASCT) for MM relapse. A systematic review of the literature was performed using PubMed, Scopus, and Web of Science databases to identify cases of patients diagnosed with both MM and DLBCL. Data on patient demographics, clinical features, treatment regimens, and outcomes were extracted. Additionally, bioinformatics analysis was conducted using publicly available genomic data from cBioPortal and IntOGen to identify driver gene mutations in MM and DLBCL. Functional and pathway enrichment analysis was performed with KEGG and Gene Ontology (GO) databases. RESULTS: The case report highlighted a complex clinical course where the patient initially responded well to R-CHOP chemotherapy for DLBCL, achieving remission, but later relapsed with MM, treated with ASCT and lenalidomide. The systematic review revealed 14 eligible studies in which MM and DLBCL often occur in older patients, either simultaneously or sequentially, with variable treatment responses, including complete remission, partial remission, or relapse. The bioinformatics analysis identified several shared function and cancer-related pathways between two cancers including interleukin and cytokine-mediated signaling pathways, regulation of cell cycle, neurotrophin signaling pathway, FOXO signaling pathway, Epstein Barr virus infection, and viral carcinogenesis. CONCLUSION: This study provides valuable insights into the dual occurrence of MM and DLBCL, emphasizing the importance of tailored treatment approaches. The driver mutations identified highlight overlapping oncogenic pathways rather than implying a shared clonal origin, and may inform future studies exploring their biological and clinical implications. Further research into these shared molecular mechanisms could lead to more effective treatments for patients with coexisting MM and DLBCL.

Bioinformatics analysis↗

PubMed2025

Unusual relapse dynamics in EGFR-mutated lung adenocarcinoma uncovered by genomic profiling: Insights from a case report.

Synchronous or metachronous multiple NSCLCs challenge clinical practice, particularly in distinguishing multiple separate primary lung cancers (SPLC) from intrapulmonary metastasis (IPM) for accurate staging and management. Here, we present a unique case of three resected lung adenocarcinomas (LUAD) from a single patient collected at different time points, all harboring the same EGFR p.L858R somatic driver mutation but exhibiting distinct clonal trajectories. Whole exome sequencing (WES) analysis revealed that the first tumor was an independent primary tumor, while the latter two tumors were clonally related. Our findings highlight the complexity of tumor progression and provide insights into clonal heterogeneity. This report underscores the importance of genomic profiling for discriminating SPLC from IPM and emphasizes that the detection of a single shared driver mutation is not sufficient to prove metastasis.

Humans↗

PubMed2026

A guide to understanding tumour evolution through the lens of population genetics.

Every cancer carries the history of its own evolution, hidden in its genome. Modern DNA sequencing can catalogue millions of mutations and profile tumours across space and time, but sequencing alone struggles to answer the questions that matter most: when did key adaptations emerge, how strongly were they selected, why do some tumours relapse whereas others do not, and how will the cancer evolve next? The reason is fundamental: sequencing is a snapshot, whereas evolution is a dynamic process. Bridging this gap requires moving beyond descriptive cancer genomics towards quantitative evolutionary inference. In this Review, we argue that population genetics provides the mathematical framework needed to extract evolutionary dynamics from cancer genomes. We show how models of mutation, selection and drift transform allele frequencies from descriptive measurements into quantitative estimates of clonal fitness and evolutionary timings. We discuss how these principles extend to epigenetic inheritance, plasticity and ecological interactions within the tumour ecosystem, and examine the assumptions and limitations for their application to modern sequencing data. By reframing cancer genomes as quantitative records of evolutionary processes rather than catalogues of mutations, researchers have used population genetics to provide a foundation for understanding - and ultimately predicting - the trajectories of cancer evolution.

Journal Article↗