We report the first Japanese case of hereditary breast and ovarian cancer(HBOC)carrying 2 germline pathogenic variants (GPVs)in the BRCA2 gene. Genetic testing of the BRCA1 and BRCA2 genes was performed in a young woman with HBOC and 2 GPVs were identified in the BRCA2 gene. Since simultaneous GPVs in both parental alleles(ie, trans)in the BRCA2 gene is diagnostic of Fanconi anemia, which is characterized by bone marrow dysfunction and susceptibility to malignancy, we genetically tested her relatives. The same variants were revealed, and both variants were located in the cis position. For patients with multiple GPVs in the BRCA2 gene, we should consider genetic testing of the relatives to confirm whether the variants are located in the cis or trans position under appropriate genetic counseling.

Microsatellite instability(MSI)testing is performed in cancer patients to determine the indication for chemotherapy with immune checkpoint inhibitors. We report on our scheme to ensure that Lynch syndrome patients are offered the opportunity for genetic counseling and genetic testing. Two hundred and eight cancer patients(107 males and 101 females, 20- 87 years, mean 63.3 years)underwent MSI testing at our hospital between February 2019 and November 2021. From February 2019 to December 2020, the MSI testing was performed with a consent document that included a commentary on Lynch syndrome, and the results were explained only by the attending cancer doctors. Eleven(8.6%)of the 136 cases had MSI-high, but none of them led to a visit to the genetic medicine department. The Genome Center in our hospital, which was operational from April 2020, undertook information sharing by multiple professions and established a system to provide appropriate support to cancer doctors. Consecutively, 72 MSI tests were performed between January and November 2021, and 2 patients(2.8%)with MSI-high(1 with endometrial cancer and 1 with colorectal cancer)were referred to the Department of Clinical Genetics for genetic counseling. Through genetic testing, both were diagnosed with Lynch syndrome, and information on future surveillance and health care for blood relatives was provided.

Recent evidence suggests that the targeting of membrane transporters specifically activated in cancer stem cells (CSCs) is an important strategy for cancer therapy. The objectives of the present study were to investigate the ion channel expression profiles in digestive CSCs. Cells strongly expressing CSC markers, such as ALDH1A1 and CD44, were separated from the human esophageal squamous cell carcinoma, gastric cancer, and pancreatic cancer cell lines using fluorescence-activated cell sorting, and CSCs were identified based on tumorsphere formation. Messenger RNA levels of CSC markers were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to anticancer agents. The microarray analysis revealed that the expression of transient receptor potential vanilloid 2 (TRPV2), voltage-gated calcium channels (VGCCs), and voltage-gated potassium channels (VGKCs) were upregulated in esophageal, gastric, and pancreatic CSCs, respectively, compared with non-CSCs. The TRPV2 inhibitor tranilast, VGCCs inhibitors amlodipine and verapamil, and VGKC inhibitor 4-aminopyridine exhibited greater cytotoxicity in CSCs compared with non-CSCs, and their inhibitory effects were also confirmed in a xenograft model in nude mice. Taking these results, phase I/II study to investigate clinical safety and efficacy of neoadjuvant combination chemotherapy of tranilast in advanced esophageal squamous cell carcinoma (TNAC study) is ongoing. These researches identified a role of ion channels in the persistence of CSCs and suggested that their inhibitors may have potential as a therapeutic agent for digestive cancers.

A 46-year-old man was diagnosed with chronic myeloid leukemia (CML) in chronic phase. He was treated with imatinib, nilotinib, and dasatinib, but failed to achieve a complete cytogenetic response (CCyR). After tyrosine kinase inhibitor therapy, F317L BCR-ABL1 kinase domain mutation was detected. At age 66, the patient started ponatinib (PON) at 45 mg/day, and achieved CCyR within three months. Subsequently, PON was tapered to 15 mg once weekly due to arterial-occlusive events. PON was discontinued after a 3-year deep molecular response (≥ MR4.5). However, the patient lost MR4.0 within two months, and PON (15 mg once weekly) was restarted. He achieved MR4.0 again within one month, and then a deeper molecular response (MR5.0) after starting dialysis therapy at the same PON dose. The trough value of PON (15 mg once weekly) was 5.8 ng/ml, which suppressed F317L mutation in the CML clone. Currently, the patient is 77 years old and is sustaining MR5.0. Chronic renal failure may cause hyperabsorption and metabolic retardation in patients receiving PON. Initiation of hemodialysis may improve homeostasis resulting in enhanced anti-tumor immunity against CML.

In acute myeloid leukemia (AML), EVI1 rearrangement represented by inv(3)(q21q26) or t(3;3)(q21;q26) causes EVI1 overexpression via structural rearrangement of an enhancer, and confers poor prognosis. My colleagues and I performed a mutational analysis of EVI1-rearranged myeloid neoplasms and identified SF3B1, a core RNA splicing factor, as the most commonly co-mutated gene. Indeed, latent leukemia development in transgenic mice bearing the humanized inv(3)(q21q26) allele was significantly accelerated by co-occurrence of Sf3b1 mutation. Intriguingly, we found that this SF3B1 mutant induced mis-splicing of EVI1 itself, which generated an aberrant EVI1 isoform with in-frame insertion of 6 amino acids near the DNA-binding domain of EVI1. This aberrant EVI1 isoform exhibited DNA-binding activity different from wild-type EVI1 and significantly enhanced the self-renewal capacity of murine hematopoietic stem cells. We also identified the cryptic branch point and exonic splicing enhancer required for this EVI1 mis-splicing induced by the SF3B1 mutant. These data provide a basis for further elucidation of the molecular mechanism and potential therapeutic candidates for EVI1-rearranged AML.

The treatment outcomes for adult Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) have improved with the introduction of pediatric protocols. On assessing long-term survivors of chemotherapy who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), it was found that these patients had good performance status and few complications. Therefore, in the first complete remission (1CR) of ALL, allo-HSCT is indicated for patients in whom the results of chemotherapy are predicted to be poor. In adolescent and young adult (AYA) patients with ALL, allo-HSCT is recommended in the 1CR if end of consolidation measurable residual disease (MRD) is positive. In adults with ALL (non-AYA patients), if end of induction MRD is negative, chemotherapy should be continued and allo-HSCT is not recommended. In the future, it is necessary to perform a comprehensive evaluation of individual patients that considers MRD, as well as the initial tumor burden and biological features of leukemic cells.

Information about genetic mutations that accumulate in each subtype of malignant lymphoma has been reported. Identification of mutations is predicted to become more crucial not only for a definitive diagnosis but also for selecting effective targeted therapies and analyzing detectable residual diseases. However, in the clinical environment of malignant lymphoma, DNA samples might be difficult to obtain, and longitudinal sample collection throughout disease development and/or remission is exceedingly difficult compared to leukemia sectors. Liquid biopsy is a new strategy of tumor biopsy that detects aberrant tumor-derived genes from a patient's plasma, cerebrospinal fluid, or other body fluids. With advances in genetic analysis methods, reports are accumulating on the usefulness of liquid biopsy in diffuse large B-cell lymphoma, central nerves system lymphoma, Hodgkin lymphoma, and other types of lymphoma. This method has the potential to significantly change the way of ML diagnosis and followed up in daily practice, and its development is a great deal of attention.

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Remarkable effort has been exerted in the classification of DLBCL and the development of its corresponding treatment. The prognosis of patients with DLBCL receiving rituximab combination chemotherapy significantly improved in the early 2000s. However, approximately 40% of patients still develop recurrence, and the prognosis of these patients is extremely poor. Recently, the use of polatuzumab vedotin and CAR T-cell therapies has improved patient prognosis. However, it is extremely important to identify the patient group who can benefit from the efficacy of these treatments. In relation to this, the molecular pathogenesis of DLBCL should be further evaluated. Recent advancements in the genetic analysis technology have led to the discovery of unknown genetic abnormalities and gene expression patterns. The elucidation and subdivision of the molecular pathology based on these findings will be the foundation of future personalized medicine.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell neoplasms characterized by bone marrow failure with a propensity to develop into acute myeloid leukemia (AML). Recent advances in genome-wide analyses have enabled identification of most somatic gene mutations responsible for MDS, and multiplex gene-panel testing for hematological malignancies will be available soon. Thus, identification of genetic abnormalities is now enabling precise diagnosis and risk-stratification of MDS. Recently, two diagnostic classification systems for MDS have been published as updates to the previous WHO classification of myeloid tumors. The IPSS-M has also been proposed as a new risk-stratification system based on genetic abnormalities and known prognostic factors. Following identification of pathological processes in MDS, therapeutic agents that can alter the course of disease, including azacitidine and lenalidomide, were approved and became available in Japan. Several novel therapeutic agents are under development as well. This paper will discuss updated diagnostic and risk-stratification systems, as well as standard treatment strategies for MDS.

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML) in the chronic phase. However, only 50-60% of patients stay on the same TKI for 5 years, and the long-term progression-free survival rate is significantly reduced if an early molecular response is not achieved. Possible mechanisms of therapeutic resistance against BCR::ABL1 dependent clones include point mutations in the ABL1 kinase domain, BCR::ABL1 splicing variants, BCR::ABL1 overexpression, and altered pharmacokinetics by the ABC transporter. Ponatinib, the most potent inhibitor among TKIs, and the STAMP inhibitor asciminib are important drugs for overcoming BCR::ABL1-dependent resistance.

Anthracycline- and cytarabine-based intensive combination chemotherapies are considered the backbone therapy for patients with acute myeloid leukemia (AML). Although chemotherapy leads to long-term remission and cures many patients with AML, it can induce DNA damage/stress due to acute/chronic toxicities, acquired resistance, relapse, and therapy-related malignancies. Introduction of molecularly targeted agents with less systemic toxicities has considerably improved the scope of treatment, particularly in elderly and frail patients. However, outcomes of TP53-mutated myelodysplastic syndrome (MDS) and AML, a distinct group of myeloid disorders, have not improved irrespective of the treatment used (median overall survival, 5-10 months). In this review, we discuss the biological and clinical significance of TP53 mutations in malignancies, while particularly focusing on MDS/AML, and emerging therapies for TP53-mutated MDS/AML. Rationally designed novel treatment strategies are expected to improve the clinical outcomes of TP53-mutated MDS/AML.

FMS-like tyrosine kinase 3 (FLT3) mutation is present in 25% of acute myeloid leukemia (AML) cases. It is associated with poor prognosis due to a high relapse rate and short remission duration. Consequently, various FLT3 inhibitors were developed. Two second-generation FLT3 inhibitors, including gilteritinib and quizartinib, are used for treating relapsed/refractory FLT3-mutated AML. Additionally, in May 2023, quizartinib was approved for newly-diagnosed FLT3-mutated AML, in combination with standard remission induction, consolidation, and maintenance therapies based on a phase 3 trial. Furthermore, high relapse rates were observed even in patients who underwent allogeneic hematopoietic cell transplantation while in their first complete remission, and post-transplant maintenance therapy using oral FLT3 inhibitors has been tried. This review summarizes breakthroughs in treatments of FLT3-mutated AML aiming for a better prognosis.

The process of RNA splicing plays a pivotal role in gene expression and genetic information modification by converting pre-mRNA into mature mRNA. Dysregulation of this process has been associated with aberrant gene expression and function, leading to hematopoietic malignancies. Through recent clinical and mouse model analyses, insights have been gained into the mechanisms underlying splicing factor mutations that aid in myelodysplastic syndrome and acute myeloid leukemia. These mutations affect genes that modulate diverse cellular processes, including chromatin regulation, transcription factors, proliferation signaling, and inflammation pathway. The relationship between aberrant splicing and cancer remains unclear despite progress in understanding the functional consequences of splicing factor mutations. This review focuses on the mechanisms of disease development because of splicing factor mutations and their potential mechanism-based therapeutic applications.

Craniopharyngiomas(CPs)are primary brain tumors that emerge from the remnants of Rathke's pouch. Despite their histologically non-malignant nature, the proximity to major blood vessels and hypothalamus, as well as the infiltrative growth, make total resection challenging. CPs are classified into two pathological subtypes: adamantinomatous(ACP)and papillary(PCP). CTNNB1 mutations were detected in ACPs, and the BRAF V600E mutation was detected in PCPs. Although both subtypes are epithelial tumors, they have different genetic profiles, clinical presentations, imaging findings, and histopathology. They are mentioned as independent chapters in the World Health Organization Classification of Tumors of the Central Nervous System, 5th edition. In 2023, a prospective clinical trial investigating a BRAF/MEK inhibitor for craniopharyngioma with BRAF mutations demonstrated marked tumor shrinkage. Currently, attempts are being made to elucidate the predictors of BRAF mutations to facilitate the use of neoadjuvant chemotherapy for craniopharyngioma. Additionally, the management of craniopharyngiomas requires the development of a surgical strategy that considers radiation and molecular-targeted therapies.

Germ cell tumors(GCT), which predominantly emerge in the early to middle teenage years among males, affect the pineal gland, followed by the neurohypophysis, often presenting with site-specific symptoms. Diagnosis hinges on imaging, tumor markers(HCG and AFP), and pathological evaluation. The radiation dose/coverage and chemotherapy intensity are tailored to the distinction between the germinoma and non-germinoma types. Surgical resection is reserved for residual non-germinomas. Biological investigations have revealed frequent mutations in the RAS, MAPK, and PI3K pathways, with no obvious structural variations. These mutations are more prevalent in germinomas than in non-germinomas. Germinomas exhibit a strikingly low methylation status across the genome, mirroring the state of primordial germ cells(PGC), deemed as the cells of origin. Mitosis/meiosis-related genes are highly expressed in germinoma, which is another supporting evidence of PGCs as cells of origin. In contrast, non-germinomas display transcriptomic features that differentiate them into tissue formation and organogenesis. Frequent copy number alterations are another hallmark of GCTs. Among these, 12p gain has been identified as a negative prognostic factor in non-germinomas. Pathologically confirmed tumor cell content serves as a poor prognostic indicator in germinomas and requires external validation as a reliable marker. Given the significant long-term sequelae stemming from treatment burdens in vulnerable young patients, a need for targeted therapy has arisen. Ongoing genomic studies are exploring the pathogenesis and uncovering potential leads for the establishment of precision medicine.

In the fifth edition central nervous system tumours volume of the WHO Classification of Tumours series, gliomas, glioneuronal tumors, and neuronal tumors are divided into six groups. The term "circumscribed" is used to refer to a relatively contained growth pattern, as compared to other inherently "diffuse" tumors. Circumscribed astrocytic gliomas include six types: pilocytic astrocytoma, high-grade astrocytoma with piloid features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, and astroblastoma, MN1-altered. The vast majority of circumscribed astrocytic gliomas harbor genetic alterations in the mitogen-activated protein kinase pathway. Here, we review the circumscribed astrocytic gliomas, including etiology, clinical and imaging features, pathology and molecular genetics, treatment, and prognosis. This study will lead to better understanding of these newly classified tumors.

Pediatric-type diffuse high-grade glioma is a new tumor class defined in the 5th edition of the WHO Classification of Tumors of the Central Nervous System(WHO2021). The class includes the following four tumor types: diffuse midline glioma, H3 K27-altered; diffuse hemispheric glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; and infant-type hemispheric glioma. Genetic detection of histone H3 mutations as well as detection of fusion genes and even methylation classifiers may be necessary to diagnose these tumors. Therefore, understanding their clinical and radiographical features is vital. Urgent establishment of new treatments is necessary for diffuse midline glioma, H3 K27-altered, as it is associated with very poor prognosis and is generally resistant to temozolomide. In this chapter, we focus on the clinical, radiographical, pathological, and molecular features of pediatric-type diffuse high-grade gliomas and introduce promising new treatments for diffuse midline glioma, H3 K27-altered.

In the 5th edition of the WHO classification, medulloblastomas, which are representative pediatric brain tumors, are categorized into four groups: WNT, SHH-TP53 wild, SHH-TP53 mutant, and non-WNT/non-SHH, based on their molecular background. While the histopathological findings still hold importance in predicting prognosis, the histopathological classification is no longer utilized in this edition. SHH medulloblastomas are further subdivided into two groups based on the presence or absence of TP53 mutation, as their clinical characteristics and prognosis differ. Group 3 and Group 4 medulloblastomas, recognized as distinct molecular groups in clinical practice, are combined into a single group called "non-WNT/non-SHH", because they lack specific molecular pathway activation. Furthermore, based on methylation profiling, dividing SHH medulloblastoma into four subgroups and non-WNT/non-SHH medulloblastoma into eight subgroups was proposed. Understanding the unique clinical characteristics and prognosis associated with each group is crucial. However, it is important to acknowledge that our current understanding of prognosis is based on treatment approaches guided by clinical risk factors such as postoperative residual tumor volume and the presence of metastatic disease. This molecular-based classification holds promise in guiding the development of optimal treatment strategies for patients with medulloblastoma.

Schwannomas are benign capsular tumors originating from Schwann cells. Although the majority are sporadic, they also occur within tumor predisposition syndromes, such as neurofibromatosis type 2, schwannomatosis, and Carney complex. Since the 5th edition of the World Health Organization(WHO)Classification of Tumors of the Central Nervous System was published, the description of grades has changed from Roman numerals to Arabic numerals. However, as in the 4th edition, it is still a WHO grade 1 benign tumor. There are several other subtypes of schwannomas in addition to the conventional type, and five subtypes have been specifically described in the 5th edition. "Melanocytic Schwannoma" in the 4th edition is now called "malignant melanotic nerve sheath tumor" in the 5th edition and is classified as a different tumor from schwannoma. Although the 5th edition places greater emphasis on genetic diagnoses, it is not essential for diagnosing schwannomas, and histological and clinical diagnoses remain equally crucial. Furthermore, after publication of the 5th edition in September 2022, an international consensus group renamed "neurofibromatosis type 2" as "NF2-related schwannomatosis." This article describes the shifts between the 4th to the 5th edition of the WHO Classification of Tumors of the Central Nervous System, along with additional clarifications, and offers the latest insights into treatment modalities for schwannomas and NF2.

In the World Health Organization Classification of Brain Tumors Fifth Edition, mesenchymal non-meningothelial tumors involving the central nervous system are divided into three major categories: soft tissue tumors, chondro-osseous tumors, and notochordal tumors. Soft tissue tumors are classified into four groups: fibroblastic and myofibroblastic tumors, vascular tumors, skeletal muscle tumors, and tumors of uncertain differentiation. This article will focus on solitary fibrous tumors(SFTs), which are frequently encountered clinically and continue to undergo classification revisions in the 5th edition, and outline the three newly added histological diagnoses. Although SFTs and hemangiopericytomas occur throughout the body, including the central nervous system, nomenclatures have been different between the classifications of "Tumours of Soft Tissue and Bone" and "Tumours of the Central Nervous System." The latest nomenclature is "SFT" in accordance with the nomenclature of bone and soft-tissue tumors. In addition, three new diagnoses, which are intracranial mesenchymal tumor FET-CREB fusion-positive, CIC-rearranged sarcoma, and primary intracranial sarcoma DICER1-mutant, have been defined based on genetic abnormalities in tumors of uncertain differentiation.