A current broad spectrum of genomic studies on acute myeloid leukemia (AML) has demonstrated that a gene encoding for DNA methyltransferase, specifically DNA methyltransferase 3 alpha (DNMT3A) is frequently mutated. However, DNMT3A variants are present in elderly healthy individuals and patients with AML in complete remission, which suggests that DNMT3A mutations may contribute to pre-leukemic clonal hematopoiesis. Although DNMT3A mutation has been thought to play a pivotal role in AML pathogenesis through the loss of DNA methylation functionality, other potential disease-related mechanisms are poorly understood. We identified that DNMT3A Arg882 mutation has two distinct mechanisms for developing clonal hematopoiesis and leukemia: (1) DNA methylation-dependent effect, which caused up-regulation of the anterior Hoxb cluster and many hematopoietic stem cell (HSC) -related genes, with hypo-methylation of the promoter-associated CpG island; and (2) DNA methylation-independent effect with enhanced recruitment of polycomb repressive complex 1 (PRC1) that subsequently suppressed the expression of an array of differentiation-associated genes. Through these mechanisms, DNMT3A mutations were shown to inhibit the differentiation of HSCs and leukemic cells. These results identified PRC1 as a promising candidate for the development of therapeutic strategies in mutant DNMT3A-associated AML. Here, we review recent studies on AML with a focus on the clinical features and functional roles of DNMT3A mutations, and discuss future challenges to effectively cure DNMT3A mutation-associated hematopoietic disorders.

The outcome of treatment-refractory and/or relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis of these cases remains poorly understood. Here, we report comprehensive profiling of 121 cases of pediatric T-ALL using RNA sequencing and/or targeted capture sequencing through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), which accounted for 3.9% (7/181) of the total examined pediatric T-ALL cases, had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell pre-commitment, establishment of T cell identity, and post-β-selection maturation with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and induced cell proliferation on constitutive expression in mouse stem/progenitor cells, resulting in a maturation block. Our findings highlight the unique role of SPI1 fusions in high-risk pediatric T-ALL.

Histone H3 lysine 27 tri-methylation (H3K27me3) -dependent transcription regulation is a fundamental process of gene control. Although EZH2 mutation is observed in certain lymphoma types, many other cancers show global H3K27me3 accumulation irrespective of mutation. However, the underlying mechanisms of gene silencing and therapeutic efficacies of epigenetic drugs remain unclear. In this study, we showed that globally-accumulated H3K27me3 is induced by both cis-bound EZH1 and EZH2 in mature lymphocyte-derived malignancies. Mutual interference and compensatory functions of co-expressed EZH1/2 rearrange the genome-wide distribution, establishing restricted chromatin and gene expression signatures. Using novel EZH1/2 dual inhibitors, we found that both EZH1 and EZH2 are required for the maintenance and induction of H3K27me3. The synthetic lethality of targeting EZH1 and EZH2 was observed in lymphoma models and primary adult T-cell leukemia/lymphoma (ATL) cells harboring H3K27me3 accumulation. This heritable EZH1/2 dysfunctional state was epigenetically imprinted at the virus-infected, immortalized phase. EZH1/2 dual inhibition could eliminate infected cell populations more effectively than EZH2 inhibition. Regarding the frequent observation of H3K27me3 accumulation in advanced-stage and early-phase malignant progenitors, the emerging EZH1- and EZH2-dependent epigenetic reprograming is an incipient process of fate decision within developmental pathways of cancers.

Comprehensive genomic and transcriptome analyses using next-generation sequencing(NGS)analysis has lead a discovery of a variety of novel driver gene mutations and new therapeutic targets for cancer patients, and has remarkably improved outcome of the patients through the development novel molecular targeting drugs. Even so, in so-called intractable or refractory cancers, those "druggable"alterations common to the diseases are rarely found due to the high diversity of the tumor. Furthermore, most of molecular target therapy is known to acquire the resistance to the drug by means of multiple factors such as up-regulation of the partially inhibited pathway, mutation of the target, activation of alternative pathways, histological translocation, and oncogene de-addiction. Understanding of intra-tumoral heterogeneity and tumor-stromal crosstalk in tumor microenvironment with consequence of biological network re-construction are also of key importance to overcome the resistance. These suggest the limitation of mono-layer OMIC approach focusing on genome and/or cancer cell alone to identify truly effective therapeutic target and biomarker. Under these circumstances,"Trans-OMICS" concept has emerged as a novel approach to clarify a global biochemical network across multiple omics layers(eg genome, transcriptome, proteome, and metabolome)directly correct with a variable phenotype by use of both multi-omic measurements and computational data integration. This approach has great potential for drug discovery and clinical implementation of omics-based cancer medicine. We introduce here the outline of technologies and analysis for Trans-OMICS approach, and review for the recent studies in oncology research with showing our recent attempt.

Sarcoma is well-known rare cancer with few therapeutic options. Recent comprehensive genomic analyses of adult soft tissue sarcoma revealed few somatic mutations and massive copy number variations(CNVs)by the specific chromosomes. Those features are quite different from the genomics of carcinoma such as lung and colon cancers in which driver and passenger mutations play a central role in the pathogenesis. Furthermore, it has been demonstrated that substantial population of sarcoma patients has pathological germline variants of cancer predisposition genes. These findings imply that, in addition to somatic mutations, inherited germline variants may play a role in the disease state of sarcoma via dosage effects. On this basis, we also discuss on the prospect and limitation of the precision medicine of sarcoma.

Development of molecular targeted drugs has achieved remarkable improvement of systemic cancer therapy. Recently, the several molecular targeted drugs have become available which associated with the status of responsible genes for hereditary cancer syndrome. These drugs would allow to establish specific strategy for hereditary cancer syndrome or sporadic cancers with similar biological phenotype with hereditary cancer. Genetic tests for the diagnosis of hereditary cancer syndrome will have the meaning of biomarker for predicting the efficacy of these molecular targeted drugs. This review summarized the molecular targeted drugs including immune checkpoint inhibitors with potential effects for hereditary cancer syndrome, such as anti-PD-1 antibody for Lynch syndrome, PARP inhibitor for hereditary breast and ovarian cancer syndrome, multi-kinase inhibitor for multiple endocrine neoplasia type 2.

A 73-year-old man with left parotid gland swelling over 2 months was referred to our hospital in March 201X. Purpura on the lower legs had been recurrent for >20 years. Biopsy of the parotid gland demonstrated diffuse infiltration of abnormal lymphocytes that were negative for CD10 and positive for CD19, CD20, and κ-chain. The Ki-67 positivity was <10%; lymphoepithelial lesions were observed. The patient was diagnosed with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Chromosome analysis revealed t (X;14) (p11.2;q32), and fluorescence in situ hybridization (FISH) of metaphase spreads showed three signals of the immunoglobulin heavy chain (IGH) gene on the derivative chromosomes X and 14, besides the normal chromosome 14. CT findings of parotid glands were suggestive of Sjogren syndrome, and biopsy of the purpura on the leg demonstrated leukocytoclastic vasculitis. In the literature, only seven patients with lymphoma and t (X;14) translocation have been reported. Of these, five patients had MALT lymphoma, one had nodal marginal zone lymphoma, and one had diffuse large B-cell lymphoma. In all patients, lymphoma evolved from previous autoimmune diseases. It is suggested that MALT lymphoma with the t (X;14) translocation forms a new entity of lymphoma.

　Although cancer treatment has dramatically improved with the development of molecular-targeted agents over the past decade, identifying eligible patients and predicting the therapeutic effects remain a major challenge. Because intratumoral heterogeneity represents genetic and molecular differences affecting patients' responses to these therapeutic agents, establishing individualized medicine based on precise molecular pathological analysis of tumors is urgently required. This review focuses on the pathogenesis of oral squamous cell carcinoma (OSCC), a common head and neck neoplasm, and introduces our approaches toward developing novel anticancer therapies particularly based on clinical molecular pathogenesis. Deeper understanding of more precise molecular pathogenesis in clinical settings may open up novel strategies for establishing individualized medicine for OSCC.

A 69-year-old man visited a doctor because of systemic lymphadenopathy. Peripheral blood examination revealed leukocytosis, anemia, and decreased platelet count (WBC, 103,060/µl; lymph, 92.2%; Hb, 8.9 g/dl; and Plt, 4.1×104/µl). Bone marrow biopsy revealed that approximately 70% of nucleated cells were small, mature lymphoid cells with positive immunostaining for CD5, CD20, and CD23. He was diagnosed with chronic lymphocytic leukemia (CLL). The IgH/CCND1 translocation and ATM locus loss in 20% and 95% peripheral cells, respectively, were detected by fluorescence in situ hybridization. Immunostaining revealed that cyclin D1 was positive in approximately 30% bone marrow cells. As the positive rate of CCND1 fusion signal was low, the diagnosis of mantle cell lymphoma was excluded. In contrast, signals of ATM locus deletion were detected in most tumor cells. Therefore, we assessed that IgH/CCND1 translocations occurred during the natural clinical course of CLL with ATM locus deletion from the onset of disease. The secondary IgH/CCND1 translocation in CLL is rare, and all reported cases with such translocations received treatments with alkylating agents. This is the first report regarding secondary IgH/CCND1 translocation during the natural clinical course of CLL and may provide insights into CLL pathogenesis.

Carcinoma with elevated SRC expression is associated with distant metastasis and drug resistance. We report 2 cases of SRC amplification observed after retrospective comprehensive genomic sequencing. Case 1 was a 62-year-old man who had RAS wild-type stage IV carcinoma of the sigmoid colon with multiple liver metastases in both lobes. He underwent low anterior resection and systemic chemotherapy was initiated to treat the unresectable multiple liver metastases. Case 2 was a 73-yearold man who had RAS wild-type stage IV carcinoma of the descending colon with metastasis in the lateral segment of the liver. He underwent left hemicolectomy and lateral segmentectomy. He subsequently underwent open radiofrequency ablation and systemic chemotherapy to treat a hepatic recurrence. Several previous studies have found that molecular targeted therapy with tyrosine kinase inhibitors is effective against colorectal cancer with elevated SRC expression. This suggests that the results of comprehensive genomic sequencing may support the implementation of new treatments.

Epigenetic alterations, represented byaberrant DNA methylation, are present in gastrointestinal cancers. Detection of cancer- specific DNA methylation can be used to detect cancer, and detection of colon cancer-specific aberrant DNA methylation is alreadyapproved byFDA. Aberrant DNA methylation is potentlyinduced bychronic inflammation, and also is accumulated in normal tissues before a cancer develops. In gastric cancer, potential of cancer risk diagnosis bymeasurement of aberrant DNA methylation in normal gastric mucosae has been clinically demonstrated. Therapeutically, DNA demethylating agents have been alreadyapproved for hematological tumors byFDA, and promising results in clinical trials against gastrointestinal cancers have been reported. Also, histone deacetylase inhibitors have been already approved for hematological tumors, and clinical trials against gastrointestinal cancers have been reported. Selection of right dose, schedule, combination, and patients is the keyto future success.

The prognosis of multiple myeloma (MM) has been improved due to the introduction of novel agents like proteasome inhibitors and immunomodulatory drugs (IMiDs). However, some cases are refractory to the use of novel agents, and the prognosis of such cases is poor. A 53-year-old male was diagnosed with MM and categorized as follows: Bence-Jones protein lambda type MM, Durie-Salmon IIIA, international staging system (ISS) stage II, and revised ISS stage II. Mutations in K-RAS and IGH/FGFR3 translocation were detected at diagnosis. His tumor was refractory to seven therapeutic regimens including bortezomib, IMiDs (lenalidomide, thalidomide, pomalidomide), conventional chemotherapy, and radiation therapy. N-RAS mutations, CKS1B gains, and C-MYC split signals were detected after treatment. We performed high-dose melphalan/autologous stem cell transplantation (HD-MEL/ASCT) as a salvage therapy and achieved very good partial response. The correlation between K-RAS mutations and poor prognosis or between N-RAS mutations and reduced sensitivity to bortezomib is reported. However, RAS mutations are reported as a favorable factor for HD-MEL/ASCT. In general, mutations of both the K-RAS and N-RAS are known to be mutually exclusive. This rare MM case has mutations in both K-RAS and N-RAS, and the possible relevance of these mutations to both the refractoriness to novel therapies and sensitivity to HD-MEL/ASCT is suggested.

Genome editing technology can alter the genomic sequence at will, contributing the creation of cellular and animal models of human diseases including hereditary disorders and cancers, and the generation of the mutation-corrected human induced pluripotent stem cells for ex vivo regenerative medicine. In addition, novel approaches such as drug development using genome-wide CRISPR screening and cancer suppression using epigenome editing technology, which can change the epigenetic modifications in a site-specific manner, have also been conducted. In this article, I summarize the current advances and future prospects of genome editing technology in the field of biomedicine.

Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety ofhuman cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion ofcancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism ofimmune evasion associated with structural variations(SVs)disrupting the 3'-untranslated region(UTR)ofthe PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers. Despite a heterogenous nature ofthese SVs, they are closely associated with a marked upregulation of PD-L1 expression, which augments tumor growth and escape from anti-tumor immunity. Here we present an overview of the regulatory mechanisms of PD-L1 expression in cancer cells, highlighting the genetic mechanisms of PD-L1 constitutive activation, with specific focus on PD-L1 3'-UTR disruption.

The Cancer Control Act approved in 2006 was amended in December 2016 by the nonpartisan federation of the National Assembly, while meeting the requests from cancer patient groups. In the chapter on the basic ideas, it is said that cancer control needs to advance the development ofthe social environment that enables cancer patients to run a smooth social life and employment support for cancer patients and promotion of cancer education are newly stated. In the chapter on the basic measures, palliative care, rehabilitation, the research on rare cancer and intractable cancer, the treatment ofchildhood cancer patients and the improvement of educational environment for those patients, and the support for private organizations and cancer patient groups are newly stated. Regarding cancer genome medical care, new legislation is expected.