Adult T-cell leukemia-lymphoma (ATL) is a malignancy of peripheral CD4+ T cells induced by human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 encodes two oncogenic viral factors, Tax and HTLV-1 bZIP factor (HBZ) in the sense and antisense strands of the provirus respectively. Both Tax and HBZ dysregulate the expression and activities of a large number of host genes and cellular signaling pathways via their multimodal functions. Tax is a potent transactivator of viral replication and various cancer-related genes in HTLV-1-infected cells; however, Tax expression is generally suppressed in ATL cells owing to its high immunogenicity. Previously, we reported that Tax is transiently expressed in a small subpopulation of ATL cells, leading to drastic changes in the host transcriptional profile. In contrast, HBZ is conserved and expressed in all ATL patients. The HBZ gene is thought to be essential in the pathogenesis of HTLV-1. It is unique in that its transcript not only encodes HBZ protein but also acts in a similar way to long non-coding RNAs. Among the functions of HBZ, activation of the TGF-β/Smad pathway is critical for proliferation of ATL cells. These multimodal actions of Tax and HBZ genes are thought to be critical for ATL leukemogenesis.

Evaluation of genetic alterations is important for diagnosis, treatment selection, and prognostic assessment in hematological malignancies, but no comprehensive genomic profiling (CGP) assays for hematological malignancies have been approved for manufacturing and marketing in Japan. We have developed a CGP assay for the analysis of genetic alterations (specifically, mutations, structural variations, and fusion genes) in 452 genes, along with a corresponding analysis and reporting system that runs on Amazon Web Services. This CGP assay, named HemeSight®, successfully detected genetic alterations with an allele frequency of 5-10% in limit of detection testing using non-clinical samples. In testing using human clinical samples, it showed high positive percent agreement (94.4% for mutations, 94.7% for IGH rearrangements [structural variations], and 100% for fusion genes) compared with established clinical tests.

Neurofibromatosis type 2 (NF2), now redefined as NF2-related schwannomatosis (NF2-SWN), is a hereditary tumor syndrome characterized by bilateral vestibular schwannomas, multiple meningiomas, and other central nervous system tumors. The revised diagnostic criteria incorporate genetic testing and consideration of somatic mosaicism, enabling a more accurate and earlier diagnosis. A strong genotype-phenotype correlation has been established: truncating mutations are associated with an earlier onset and severe clinical course, whereas missense or splice-site mutations are often linked to milder phenotypes and better functional outcomes. Immune and molecular profiling have revealed distinct subtypes of vestibular schwannomas and meningiomas, reflecting differences in tumor behavior and therapeutic responses. In young patients presenting with unilateral vestibular schwannoma, clinicians should remain alert to the possibility of NF2-SWN and consider surveillance based on progression and genetic background. Targeted therapies-including bevacizumab, brigatinib, and vascular endothelial growth factor -A vaccines-have shown promise, particularly in refractory cases. Although routine intensive surveillance is not universally required, early genetic screening and long-term follow-ups may benefit select individuals. The comprehensive integration of genetic, pathological, and immunological data is essential for advancing personalized treatment strategies for NF2-SWN.

MLL gene rearrangements cause malignant leukemia, and continue to pose challenges for both patients and their clinicians. Gene rearrangements result in fusion of MLL with more than 80 different partner genes, whose protein products constitutively activate MLL-target genes such as HOXA9 and MEIS1, thereby transforming hematopoietic progenitors into leukemia cells. Interactome analysis identified MENIN as a common associated factor for both MLL fusions and wild-type MLL. Domain mapping analysis of MLL fusion identified the MENIN binding motif and the CXXC domain as the crucial structures for leukemic transformation. The CXXC domain mediates interaction with unmethylated CpGs, which are clustered in the promoter regions. MLL-MENIN interaction leads to further association with LEDGF, which contains a PWWP domain that binds to di/tri-methylated histone H3 K36 (H3K36me2/3). The PWWP and CXXC domains confer stable binding to CpG-rich promoters containing H3K36me2/3 marks so that MLL fusion proteins are able to recognize their target genes. Thus, the protein complex assembly of MENIN, MLL fusion, and LEDGF is the critical event required for leukemia induction, which provides opportunities for drug-mediated inhibition of the MLL fusion protein complex. Small compounds that interfere with MENIN-MLL interaction have been developed by several pharmaceutical companies. Some are now in clinical trials, and one has even obtained FDA approval.

In multiple myeloma, inactive somatic mutations of UTX, a histone H3K27 demethylase and a component of the COMPASS complex, and activating BRAF V600E mutations have been reported. We generated a new mouse model in which Utx knock-out and Braf V600E knock-in were induced only in post-germinal center B cells including plasma cells. Compound mice with both mutations developed mature B-cell neoplasms such as B-cell lymphomas and myeloma-like plasma cell tumors as they aged. Analyses of malignant plasma cells revealed that the expression of Myc and myeloma-related genes was significantly increased and that epigenetic reprogramming progressed before the onset of disease. Furthermore, we proved that the function of UTX as a tumor suppressor was independent of its H3K27me3 demethylase activity. In addition, we found that CD8+PD-1+Tim-3+/- exhausted T cells were increased in tumor sites of mature B-cell neoplasms and that the prevention of excessive exhaustion could be a therapeutic option. This mouse model is a useful tool for understanding the pathogenesis of human diseases and developing novel therapeutics.

Multiple myeloma (MM) is triggered and promoted by the accumulation of genetic alterations. However, MM is highly dependent on the bone marrow microenvironment, which suggests that epigenetic deregulation plays a significant role in the pathogenesis of MM. Indeed, recent studies using next-generation sequencing have revealed epigenetic alterations in MM. Epigenetic regulation involved in the development of cancers, including MM, can either be observed across multiple cancer types or be specific to a single cancer type. The former type of regulation is associated with driver events common to multiple cancer types, and my colleagues and I have recently identified the importance of the KDM5A-mediated H3K4 methylation cycle in activating MYC-driven transcription. The latter type is closely related to lineage-restricted epigenetic programs. In MM, the B-cell differentiation factor IL-6 may partly mediate the MM-distinct epigenetic program. This article discusses epigenetic deregulation in MM, focusing on our recent findings.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) in first complete remission (CR1) has been the standard treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia. However, the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI), dramatically improved outcomes. The subsequent development of next-generation TKIs like dasatinib and ponatinib, as well as the antibody therapy blinatumomab, has further diversified treatment strategies. There is an increasing shift toward avoiding allo-SCT in pediatric patients, both in Japan and internationally. For elderly patients ineligible for allo-SCT, chemotherapy-free regimens combining TKIs and blinatumomab show promise for improving outcomes. Moreover, international studies suggest that young adults may also be able to avoid allo-SCT in CR1. In contrast, current data in Japan are insufficient to support the avoidance of allo-SCT in CR1, and caution is needed when applying findings from overseas. Future efforts should focus on establishing personalized treatment approaches, including risk-stratified transplantation eligibility.

Acute myeloid leukemia (AML) is becoming more prevalent as the Japanese population ages, highlighting the growing importance of individualized treatment based on age, comorbidities, and genetic abnormalities. This review outlines the significant transformation in AML management after the introduction of azacitidine plus venetoclax, FLT3 inhibitors, and CPX-351. It also discusses HEM-SIGHT, a next-generation sequencing panel developed in Japan that became covered by Japanese national health insurance in 2025, enabling a molecularly stratified approach to diagnosis. Despite advances in treatment, several subtypes including TP53-mutated and MECOM-overexpressing AML remain highly refractory, even with allogeneic stem cell transplantation and targeted therapies. These high-risk entities pose ongoing therapeutic challenges. The current paradigm in AML treatment has shifted toward strategic personalization, encompassing molecular abnormality identification, measurable residual disease assessment, and treatment adaptation based on these findings. To achieve wider adoption of precision medicine in clinical practice, Japan must continue strengthening its diagnostic systems, streamlining genomic testing in routine practice, and integrating these strategies with novel therapeutic development.

Recent advances in molecular genetic research, driven by the development of genomic analysis technologies, have significantly improved treatment outcomes for leukemia. In recent years, mounting evidence indicates that germline genetic background influences drug sensitivity and the risk of adverse effects, underscoring the growing importance of personalized treatment strategies. In particular, the NUDT15 polymorphism, which determines sensitivity to 6-mercaptopurine, has garnered significant attention. Notably, a low-activity variant of this polymorphism, prevalent in Asian countries, has been shown to substantially increase the risk of bone marrow suppression and other adverse effects. Pre-treatment analysis of the NUDT15 polymorphism has demonstrated utility in dose adjustment, helping to mitigate the risk of treatment-related toxicities. Studies have also explored the relationship between genetic background and late complications of leukemia treatment. Optimization of therapeutic strategies based on pharmacogenetic insights holds promise for minimizing complications while maximizing treatment efficacy for each individual patient.

Peripheral T-cell lymphoma (PTCL) is a highly heterogenous disease that accounts for 10 to 15% of malignant lymphomas. It encompasses a wide range of disease types, including nodal, extranodal, and leukemic forms. Recent molecular genetic findings about PTCL have significantly deepened our understanding of the disease, leading to the reclassification of previously distinct subtypes under a unified entity (e.g., T-follicular helper lymphoma). In terms of treatment, CHOP or CHOP-like therapy have been widely adopted as a first-line regimen. However, even in ALK-positive anaplastic large cell lymphoma, which generally has favorable outcomes, the prognosis of PTCL remains unsatisfactory. The extremely poor outcomes of relapsed and refractory disease have highlighted an urgent need for breakthrough therapies. In recent years, novel therapeutic approaches, including antibody-drug conjugates, epigenetic modifiers, and immune cell therapies, have improved clinical outcomes for some patients with PTCL. However, the optimal use of novel approaches remains unclear, and stratification based on molecular genetic findings is crucial to achieve more effective and precisely targeted treatment.

Adult T-cell leukemia/lymphoma (ATL) has a very poor prognosis with conventional multidrug chemotherapy. Lenalidomide, an oral anticancer drug classified as an immunomodulator, showed an overall response rate of 46% in a phase II clinical trial in relapsed ATL. The antibody therapy mogamulizumab showed an overall response rate of 50% in a phase II trial of relapsed C-C motif chemokine receptor 4-positive ATL. Brentuximab vedotin has yet to show clear evidence of efficacy due to the limited number of patients enrolled in phase II trials. Epigenetic therapy has also been investigated. The EZH1/2 inhibitor valemetostat showed a response rate of 48% in a phase II trial in relapsed/refractory aggressive ATL. The histone acetylation inhibitor tucidinostat also exhibited efficacy in ATL, with an objective response rate of 30.4%. This review focuses on the abovementioned molecular-targeted agents, which are all currently used in Japan.

Comprehensive genomic profiling for metastatic castration-resistant prostate cancer (mCRPC) is rapidly becoming widespread. This study sought to investigate the gene alteration profiles of Japanese patients with mCRPC. We retrospectively reviewed 80 consecutive mCRPC patients who underwent comprehensive genomic profiling tests at our institution between 2021 and 2022. All patients underwent next-generation sequencing (NGS) : FoundationOne® CDx (F1-CDx) or FoundationOne® Liquid CDx (F1L-CDx). F1LCDx was indicated for cases in which tissue specimens were older than 5 years or could not be analyzed using F1-CDx. The median patient age was 74 years. Thirty-five and 45 patients received F1-CDx and F1LCDx, respectively. At least one pathogenic variant was found in 35 (100%) who received F1-CDx and 43 (95%) who received F1L-CDx. In total, 11 and 1 patients had pathogenic variants of BRCA2 and BRCA1, respectively. Among them, 4 cases (33%) were found to be germline variants. TP53, CDK12, and PTEN were found in ＞ 20% of cases who received F1-CDx. DNMT3A, TP53, AR, and TET2 were found in ＞ 20% of cases who received F1L-CDx. The proportion of gene alteration subtypes of amplification and loss in F1L-CDx was less common than that in F1-CDx. Pathogenic variants were successfully detected in almost all F1-CDx and F1L-CDx cases in our mCRPC cohort. The total proportion of BRCA1/2 pathogenic variant patients was similar to those in previous reports.

Treatment strategies for breast cancer are becoming increasingly complex, necessitating a deeper understanding of the disease and the personalization of therapy based on biomarkers. Circulating tumor DNA(ctDNA)allows for comprehensive tumor assessment in a minimally invasive manner, and therapeutic development in this area is actively progressing. Studies evaluating ctDNA during postoperative follow-up or after neoadjuvant chemotherapy across various breast cancer subtypes have consistently shown that ctDNA detection is associated with a higher risk of recurrence, regardless of the clinical setting. Clinical trials investigating therapeutic interventions guided by ctDNA testing are currently underway. Moving forward, the development of more sensitive assay and effective therapeutic strategies is needed. The clinical application of ctDNA is expected to further advance personalized treatment in breast cancer.

Recent advancements of surgery including robotic surgery have improved the clinical outcomes of resectable solid tumors. Although preoperative chemotherapy is often performed for high-risk cancers, the risk of postoperative recurrence remains a critical issue. So far, recurrence has been monitored through periodic imaging tests; however, molecular residual disease (MRD)has caught much attention as the means to detect minimal cancerous lesions at an earlier stage. With the rapid advancements in circulating tumor DNA(ctDNA)analysis using next-generation sequencing, MRD testing is emerging as a promising tool for predicting recurrence in multiple types of cancer. Thus, in this article, we discuss the current status of MRD testing in urogenital cancers and its potential impact on future treatment strategies.

In lung cancer, circulating tumor DNA(ctDNA)analysis has already been clinically implemented, for example, to detect resistance mutations to EGFR-TKIs. Recently, as in many other cancer types, postoperative detection of molecular residual disease (MRD) has been shown to correlate with poor prognosis. This article summarizes the latest findings on MRD research in lung cancer. A literature review as of May 2024 identified 41 studies on lung cancer MRD. Although no randomized trials have yet utilized MRD to guide treatment decisions in this field, retrospective studies consistently demonstrate its utility in predicting recurrence. In Japan, prospective studies such as JCOG2111A(MRDSEEKER trial, NCT06854939), which evaluates the kinetics and detection rate of MRD using a tumor-informed personalized assay, are currently underway. Notably, recent subset analyses of ctDNA/MRD assessments before and after treatment in randomized trials on perioperative chemoimmunotherapy and adjuvant therapy have garnered significant attention. However, the sensitivity of the assays used in these studies possibly remains suboptimal for lung cancer. Future prospective trials incorporating more sensitive, second-generation assays may be warranted.

In October 2024, "Japan society of clinical oncology position paper on appropriate clinical use of molecular residual disease( MRD)testing"was issued. MRD is defined as"molecular residual disease detected by the detection of circulating tumor DNA(ctDNA)prior to the appearance of clinical, biologic, or radiologic evidence of recurrence after curative resection" and has been strongly associated with recurrence after curative resection across multiple cancer types. The attempt to develop personalized perioperative treatment based on MRD testing has been called the"liquid revolution", and competition for development is intensifying worldwide. The MRD testing is expected to be a game changer not only in terms of its validity in predicting recurrence, but also in terms of changing the framework of clinical trials for perioperative treatment development and further promoting the development of new therapies. This paper presents the current status and discusses the near future of clinical development based on MRD testing.

A 77-year-old woman was diagnosed with advanced transverse colon cancer(poorly differentiated adenocarcinoma)cT3N3H0P0, cStage Ⅲc and underwent extended left hemicolectomy in April 2020. The tumor tissue revealed RAS: wild type, BRAF: mutant type, dMMR(MLH1 deficiency)by immunochemical staining, and MSI-H by CDx. She received CAPOX as adjuvant chemotherapy after surgery. At the end of the 3 courses, she developed abdominal aortic lymph nodes recurrence( diameter 32×18 mm)and began to receive pembrolizumab therapy in August 2020. But the tumor re-grew 6 months after the start of this regimen. However the recurrent lesion was localized, radiation therapy(IMRT: 54 Gy/27 Fr) was added in combination with pembrolizumab. Two months later the tumor had shrunk significantly. As of June 2024, the patient has remained recurrence-free, suggesting that the abscopal effect may have been involved by immuno-radiotherapy in this case.

During oncogenesis and proliferation of cancer cells, numerous alterations occur in genomic DNA and mRNA, and these alterations consequently result in the production and presentation of cancer-specific epitopes(neoantigens)on cancer cell surface through the major histocompatibility complex(MHC). These neoantigens then mark cancer cells as"non-self"leading to elimination by the immune system. One of the major insights from cancer genome studies is the detection of neoantigens. Some cancer genome mutations produce neoantigens, enhancing the responsiveness to immune checkpoint blockade (ICB)therapies. The tumor mutation burden(TMB)is used as a surrogate metric for the rate of neoantigen production, and practically used as a biomarker to determine suitability of pembrolizumab, an anti-PD-1 ICB. The focus of neoantigen analysis has been on mutations in genomic DNA. However, recent studies revealed cancer-specific mRNA arising from RNA splicing also provides a source of neoantigens. These findings would provide more detailed insights into cancer immune response and improve the predictive accuracy of ICB effects. In this article, recent progress about RNA splicing-associated neoantigens is summarized.

Conventionally, hereditary tumor syndromes have been identified on the basis of clinical features, including characteristic tumor types and family history. Therefore, it is important for clinicians to consider hereditary tumor syndromes and collect detailed patient background information. However, recent advancements in genetic analyses have enabled the molecular diagnosis of these syndromes. This review addresses the recommendation of genetic counseling for affected patients and their families. In addition, the key points of the updated World Health Organization classification of central nervous system tumors are summarized.

The current main treatment goal of polycythemia vera (PV) is preventing thromboembolic and hemorrhagic complications. However, these therapeutic strategies cannot delay progression of PV. Therefore, there is an unmet need for next-generation therapeutic strategies to slow disease progression and improve survival in patients with PV. One of the most promising agents for modifying the disease course of myeloproliferative neoplasms is interferon alpha, which has been used to treat PV since the 1980s. Notably, it achieved cytogenetic or molecular responses in some patients. However, conventional interferon was not widely used due to its high incidence of adverse events and poor tolerance. Ropeginterferon alfa-2b (ropeg) is a unique, site-selective polyethylene glycol-conjugated form of recombinant interferon alpha. A phase 1/2 study of ropeg for PV patients showed low toxicity and improved tolerability, along with significant molecular response. A phase 3 randomized study (PROUD-PV/CONTINUATION-PV) revealed that treatment with ropeg continuously decreased the JAK2V617F allele burden compared to hydroxyurea and improved event-free survival (with events defined as thromboembolic events, disease progression, or death). A phase 2 study in Japanese patients with PV further confirmed the efficacy of ropeg.