Standard treatment for acute myeloid leukemia (AML) comprises (1) induction therapy with both cytarabine and anthracycline and (2) consolidation therapy that is modified according to patients' conditions, including prognostic factors. However, this strategy is not satisfactory, especially for elderly patients. Novel technologies have revealed several driver mutations of numerous critical genes in AML, which can be targeted by novel drugs; the discovery of such targetable genes and the development of novel drugs have evolved the treatment strategy for AML. We should always monitor these advances in hematology. In the United States, the FDA has already approved several new drugs for AML, including FLT3 inhibitors and IDH neoenzyme inhibitors. In Japan, gilteritinib, an FLT3 inhibitor, was also approved at the end of 2018. These promising drugs will facilitate performing "precision medicine" on patients with AML soon.

Genetic abnormalities of acute myeloid leukemia (AML) include chromosomal translocations and gene mutations. Commonly observed chromosomal abnormalities in AML are t (8;21), t (15;17), inv (16), and 11q23-related translocations. These aberrations produce RUNX1-RUNX1T1, PML-RARA, CBF-MYH11, and MLL-fusion genes, respectively, which promote leukemic stem cell formation by interfering with hematopoietic differentiation and enhancing the self-renewal capacity of hematopoietic cells. Gene mutations recurrently occur in transcription factors, signaling molecules, tumor suppressor genes, epigenetic regulators, RNA splicing factors, and cohesion complexes, with FLT3, NPM1, and DNMT3A being the most frequently mutated genes in AML. Recent studies disclosed the biological function of mutated genes and their correlation with prognosis. Based on these findings, development of novel therapeutic drugs targeting mutated genes or dysregulated genetic pathways is underway.

Although immune checkpoint blockade therapy using anti-PD-1/PD-L1 antibodies can induce durable remission in a variety of human malignancies, the mechanisms regulating the expression of PD-1 ligands(PD-L1 and PD-L2)have not been fully investigated. Recently, we newly identified structural variations(SVs)disrupting the 3'-untranslated region(UTR)of the PD- L1/PD-L2 genes in various cancers, which caused a marked upregulation of these molecules and mediated immune escape of tumor cells. Particularly, these alterations were frequently observed in virus-related lymphomas, such as adult T-cell leukemia/ lymphoma as well as Epstein-Barr virus-positive diffuse large B-cell lymphoma and extranodal NK/T-cell lymphoma. These results suggest a pivotal role of PD-L1/PD-L2-mediated immune evasion in the pathogenesis of virus-related tumors. Here we summarize the genetic alterations involving the PD-L1/PD-L2 genes in human cancers, highlighting their relevance in virusassociated tumors.

In July 2018, olaparib, an oral poly adenosine diphosphate-ribose polymerase(PARP)inhibitor, was approved for the first time in Japan as a companion diagnostic drug for the treatment of recurrent breast cancer in BRCA-positive patients. Genetic testing had been offered only to clients who met the eligibility criteria for the test, and the decision whether or not to receive the test was based on their medical and family history, tumor characteristics, and the client's preference. With the approval of olaparib as a companion diagnostic drug, genetic testing has become a part of the standard treatment protocol. Modern technology has made multiple genetic testing possible in one setting. It is therefore necessary for medical practitioners to have the knowledge and ability to take care for familiar tumors. It may be difficult to understand all the available information on genetics, but an individualized approach for each patient would be necessary in the future. Medical practitioners involved in the treatment of such patients would need adequate knowledge on genetics and genetic counseling, as well as the ability to educate and provide information to the patients and their families. If a more specialized approach is necessary, referral to an institution with a clinical genetics department is essential.

Recent development of massive parallel-sequencing technology has revealed the genetic basis of pediatric T-cell acute lymphoblastic leukemia (T-ALL). However, epigenetic profiles of T-ALL, such as DNA methylation, have not been well characterized. To describe the epigenetic landscape of T-ALL, we investigated DNA methylation profiles of 79 cases with pediatric T-ALL by using the EPIC methylation array, which allowed us to perform more profound analyses, including the OpenSea region. Moreover, we conducted combined analyses of methylation data using our previous expression and mutation data. Based on DNA methylation profiles, pediatric T-ALL was clustered into four distinct subtypes, which exhibited remarkable association with genetic signatures and expression features, as well as profiles of normal T-cell development. Furthermore, our study revealed the importance of methylation status at binding sites of polycomb-repressive complex components and transcription factors, such as SPI1, in the classification of pediatric T-ALL based on DNA methylation status. These results might be helpful in the development of new therapeutic strategies for pediatric T-ALL.

Mature T- and NK-cell neoplasms are a heterogeneous hematological malignancy. The current treatment of mature T- and NK-cell lymphoma depends on combination chemotherapy with or without auto/allogeneic hematopoietic stem cell transplantation. Recent comprehensive, integrated genetic analyses have revealed distinct genetic and molecular subgroups, which are related to different therapeutic responses. Thus, the genetic landscape of mature T- and NK-cell neoplasms is essential for the development of novel treatment modalities and offers opportunities for individualized therapy. This review aims to discuss the recent progress regarding genetic and molecular analyses of mature T- and NK-cell neoplasms toward stratified therapy.

Among the hematologic tumors, lymphoid malignancies, especially B-cell lymphomas (BLs), are categorized according to the WHO classification into a large number of entities, which are aggregates of clinically and biologically diverse diseases. It is thought that various molecular genetic abnormalities are involved in lymphoid tumorigenesis. Recent advances in genetic analysis technology have resulted in the discovery of many novel and recurrent genetic abnormalities. In particular, those associated with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma have been identified utilizing molecular pathology techniques, which is important aspect for the future development of novel therapeutic drugs and indications for clinical trials. In this section, the possibility of patient-stratification based on genetic abnormalities of DLBCL and FL, which are particularly prevalent among mature BLs, are described. I also introduce the genetic features and clinical importance of BL and MCL identified in a small number of patients in Japan.

Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.

In 2018, a total of 11 institutions was selected as the leading hospitals to promote genomic cancer medicine in Japan. In April 2019, a multiplex gene panel test will be approved by government and establishment of infrastructures is now urgently needed in hospitals which implement genomic medicine. Following infrastructures and human resources are relevant to genomic medicine; (1) Education of medical staffs who will be involved in genomic medicine, (2) Medical staffs of pathology department who can properly handle the pathology samples for sequencing tests, (3) Coordinators who assist physicians with gene test application, sample shipping, and appointments of outpatient clinic, (4) Molecular tumor board comprising a variety of medical experts(medical oncologists, pathologists, medical geneticists, bioinformaticians etc), (5) Genetic counseling system for secondary findings. In this section, I would like to introduce how those infrastructures are established in our institution.

Genomic profiling tests using next-generation sequencer have been approved in December 2018 and their reimbursement by the national health insurance system will start soon. The Ministry of Health, Labor and Welfare assigned "Core Hospitals" and "Cooperative Hospitals" as a framework to provide cancer genomic medicine in Japan. Core Hospitals perform molecular tumor board meetings, called "Expert Panel", to make therapeutic recommendation based on the profiling results in cooperation with "Cooperate Hospitals". National Cancer Center has developed an original genomic profiling system(NCC Oncopanel system)to identify genetic alterations of 114 cancer-related genes. Clinical utility and feasibility of this system is being validated by 50Core and Cooperative Hospitals within the Advanced Medical Care B system.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphoid malignancies. Several recent comprehensive genomic studies characterize the genomic alterations of each PTCL type and reveal the complexity and heterogeneity. The updated World Health Organization classification has precisely distinguished "lymphoma" from "lymphoproliferative disorder" and has included a new entity based on the tumor phenotypes. Although establishing the classifications based on genomic alterations has been difficult because of heterogeneity, the genomic alterations may support the diagnosis. Establishing genomic alterations that act as predictive markers for clinical courses and/or therapeutic targets is needed in future studies using genomic alteration information. Since patients with PTCL generally have poor prognosis, establishing the target and standard therapies is one of the major issues to be addressed. In addition to clinicopathological and genomic analyses, patient-derived xenograft models can provide these therapeutic strategies. Integration of analyzed data is considered to promote future PTCL studies, leading to improved PTCL prognosis.

Mitogen-activated protein kinase (MAPK) pathways are evolutionarily conserved kinase modules that link extracellular signals to the machinery that controls fundamental cellular processes such as growth, proliferation, differentiation, and apoptosis. The Ras/Raf/MEK/ERK MAPK pathway is one of the most studied of the mammalian MAPK pathways and has attracted intense research interest because of its critical involvement in the regulation of cell proliferation. The mutational activation of upstream signaling components that constitutively activate ERK MAPKs as seen in various primary tumor samples has validated this pathway for drug discovery. The fission yeast Schizosaccharomyces pombe is an important tool for cancer research. This well-studied model organism has enabled groundbreaking, Nobel Prize-winning discoveries and has provided insights into how both normal and cancerous cells grow and divide. We performed chemical genetic screening using a fission yeast phenotypic assay and demonstrated that ACA-28, a synthetic derivative of 1'-acetoxychavicol acetate (ACA), effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. Importantly, the growth of normal human epidermal melanocytes was less affected by ACA-28. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells oncogenically transformed with HER2/ErbB2 but not in the parental cells. Notably, the ACA-28-induced apoptosis was abrogated when ERK activation was blocked with the specific MEK inhibitor U0126. Consistently, ACA-28 more strongly stimulated ERK phosphorylation in melanoma cells as compared with normal human epidermal melanocytes. ACA-28 might serve as a promising seed compound to combat ERK-dependent cancers by stimulating oncogenic signaling.

Stress-responsive signaling pathways convert cellular stresses into various physiological responses, such as cell proliferation, apoptosis, and inflammation. Signal pathway dysfunction thus induces abnormal cellular behaviors that may lead to tumorigenesis and tumor progression, including metastasis. Tumor metastasis is the spread of tumor cells from primary lesions to other distant tissues/organs. Several types of murine model which mimic the progression of human cancer have been established for preclinical studies to understand the biology of cancer. Mitogen-activated protein kinase (MAPK) cascades are one of the stress-responsive signaling pathways and are intricately involved in both tumor promotion and suppression. Here, we present the diverse roles of apoptosis signal-regulating kinase (ASK) family molecules in tumor formation and progression. ASK family is a member of MAPK kinase kinase (MAP3K) family in the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways and comprises three family members, ASK1, ASK2, and ASK3. Accumulating evidence indicates that ASK1 controls tumorigenesis through the regulation of innate immunity and apoptosis. ASK2 also regulates tumorigenesis via apoptosis. Furthermore, analysis of the experimental lung metastasis model in mice suggests that host ASK1 deficiency attenuates tumor lung metastasis. In this symposium review, we discuss the potential roles of ASK family in the context of tumor metastasis.

Since the 1980s, zebrafish (Danio rerio) have been used as a valuable model system to investigate developmental processes because they: 1) grow outside their mothers; 2) are transparent during the embryonic stage; and 3) have organs similar to those in humans. Recently, zebrafish have emerged as a powerful model animal for studying not only developmental biology but also human diseases, especially cancer. Owing to the significant advantages of zebrafish, such as low-cost breeding, high efficiency of transgenesis, and ease of in vivo imaging and oncogenic/tumor cell induction, zebrafish offer a unique opportunity to unveil novel mechanisms of cancer progression, invasion, and metastasis. In addition, the small size of zebrafish larvae enables high-throughput chemical screening, and this advantage contributes to generating useful platforms for antitumor drug discovery. Owing to these various merits, which other model animals (such as fly, mouse, and rat) do not possess, zebrafish could achieve a unique status in cancer research. In this review, we discuss the availability of zebrafish for studying cancer and introduce recent cancer studies that have used zebrafish.

We suspected Birt-Hogg-Dubé syndrome (BHDS) from intraoperative findings of emergency operation for idiopathic hemopneumothorax. A 34-year-old man was delivered to our center due to sudden chest pain and dyspnea. Under the diagnosis of hemopneumothorax, emergency operation was performed. During surgery, multiple thin wall lung cysts of 2 to 5 mm in size were observed on the surface of all lung lobes. BHDS was suspected, but the surgery was limited to hemostasis and resection of pulmonary cyst since the diagnosis had not been established. Postoperative chest computed tomography (CT) revealed irregular shaped pulmonary cyst on the interlobar, mediastinal and diaphragm surface. Genetic analysis showed deletion in the folliculin gene confirming the diagnosis of BHDS.

We report a case of a patient with early-onset breast cancer who decided to undergo adaptation for breast-conserving surgery based on the results of genetic testing. A 25-year-old woman became aware of a lump in her left breast and visited a nearby hospital, where she was diagnosed with breast cancer. She has no personal history. Her paternal grandfather was diagnosed with rectal cancer at age 60. Ultrasonography revealed an irregularly-shaped hypoechoic mass measuring 3.8 cm in the C area of her left breast and an enlarged lymph node 2.0 cm in diameter in the left axillary area. The breast tumor was pathologically diagnosed as invasive ductal carcinoma by core needle biopsy and was immunohistochemically characterized as ER(-), PgR(-), and HER2(-), s o-called triple negative. Moreover, lymph node metastasis was confirmed by fine needle aspiration cytology. She underwent neoadjuvant chemotherapy and achieved a clinical complete response. A woman with early-onset triple negative breast cancer has a high probability of hereditary breast and ovarian cancer, with a high risk of ipsilateral second breast cancer after conserving surgery. Thus, BRCA genetic testing may be necessary before surgery. As no pathogenic mutation wasfound in BRCA 1/2 in this case, the patient underwent breast-conserving surgery followed by radiation therapy for the conserved breast. The patient remained healthy and without any recurrence 4 years and 2 months after surgery.

Practical cancer genome medicine requires large-scale data analysis for many types of biological data such as cancer driver mutations, aberrantly methylated regions, gene expression also biological knowledge from literature. Machine learning algorithms play an important role in bioinformatics of clinical oncology. In this review, we examine the applications of machine learning algorithm on recent research of cancer genome medicine. As an introduction, we consider relationship between artificial intelligence(AI)and machine learning and characterize the technical advantages of deep learning. The later part of this article examines 4 research publications within 3 domains. That includes comprehensive research about actionable mutations, novel approach for identifying activated Ras pathway and feasible methodologies to increase sensitivity of detecting cancer with cell-free DNA from 2 different research groups.

Acute megakaryoblastic leukemia in children without Down syndrome (non-DS AMKL) is considered to be a poor prognostic subtype in acute myeloid leukemia. Recently, some chimeric fusion genes were found in pediatric non-DS AMKL; therefore, we attempted to detect chimeric fusion genes RBM15-MKL1, CBFA2T3-GLIS2, and NUP98-KDM5A from 10 pediatric non-DS AMKL diagnostic samples using polymerase chain reaction and Sanger sequencing methods. Two samples were positive for RBM15-MKL1, four had CBFA2T3-GLIS2, and only one case had NUP98-KDM5A. Both RBM15-MKL1-positive patients showed long-term remission after chemotherapy. The eight RBM15-MKL1-negative patients received hematopoietic stem cell transplantation (HSCT). In four CBFA2T3-GLIS2-positive patients, three had HSCT without complete remission and two of themdied. Additional treatment stratification depending on chimeric fusion genes and development of new therapeutic drugs are required for non-DS AMKL.