Recently, pembrolizumab have been approved for advanced solid tumor with microsatellite instability-high, and nivolumab including combination therapy with ipilimumab for colorectal cancer with microsatellite instability-high, and usefulness of those 3 checkpoint inhibitors have been paid attention. Genetic testing is essential for selecting molecular-targeted drugs in colorectal cancer; however, the type of tests and their optimal timing are becoming more complicated. Hence, this article reviews the gene mutation tests used for advanced colorectal cancer, the molecular mechanism of colorectal cancer with microsatellite instability-high, the clinical development status of immune checkpoint inhibitors, and the future perspective on treatment strategy.

The whole-genome sequence(WGS)has enabled us to comprehensively uncover cancer genome alterations, including non-coding drivers, structural abnormalities including fusion genes, mutation signature, and pathogenic genome integrations. Clinical utilities of WGS include effective molecular diagnosis, promotion of drug and biomarker discovery, and genome-based cancer prevention. To install WGS in the cancer medicine platform, we should establish and maintain WGS infrastructures as a sustainable system. Moreover, empirical evaluation of clinical utilities and cost-effectiveness for the target patient population is required. Furthermore, introducing new technologies such as liquid biopsy, long-read sequencing, and artificial intelligence is essential. WGS has high potentiality for next-generation genome medicine in cancer.

According to the recently revised WHO classification, peripheral T-cell lymphomas (PTCL) can be classified into up to 30 subtypes. Because the majority of these subtypes were rare cancers, their pathophysiology was not well understood. However, technological advancements including multi-omics approaches such as genomic and gene expression analyses have made significant progress in understanding the pathophysiology of PTCL. Based on the results of these basic studies, the classification of T-cell lymphomas has been changed. Furthermore, new markers discovered through genomic analysis and gene expression analysis are being incorporated into the diagnostic processes of PTCL. Furthermore, multiple new drugs were approved to treat patients of PTCL. Clinical trials are also being carried out as first-line treatments to test the efficacy to combine these new drugs with conventional treatments.

Somatic mutations in the epigenetic regulator ASXL1 are considered a poor prognostic factor in myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). ASXL1 mutations coexist with other mutations in majority of patients, suggesting that its mutation alone is insufficient to cause cancer. ASXL1 mutations have been detected in age-related clonal hematopoiesis (CH), which has been linked to an increased risk of hematological malignancies. Therefore, ASXL1 mutations are likely to be one of the first events in the tumorigenesis process. With our most recent findings, we summarize the mechanisms by which ASXL1 mutations cause CH and hematological malignancies in this review.

We educate medical specialists in cancers including genomic medical specialist and pediatric/hematologic oncologists, understood the needs of patients at each stage of life from the pediatric~AYA generation to the elderly, and fostered advanced cancer medical personnel necessary for each phase of cancer treatment based on the patient's perspective. The 7 universities in the Kansai region collaborated with each other by taking advantage of their unique characteristics. We were able to establish an advanced cancer education course that understands the various needs and regional characteristics of cancer treatment and promotes team medicine. We have trained oncology surgeons, oncology/oncology pharmacotherapies, palliative medicine specialists, oncology pathologists, radiation oncologists, oncology pharmacists, oncology nurses, oncology cytologists, medical physicists, radiotherapy technicians(, from the 3rd period~)genomic medicine specialists, and pediatric hematology/oncology specialists. We were able to provide practical education that included hands-on training and practical training. We conducted educational activities in collaboration with multiple professions and multiple universities, contributing to society and the community. We promoted advanced research activities and achieved lots of research achievements. We were able to train many graduate students to become qualified cancer specialists. Graduates of the program were sent to medical institutions specializing in oncology.

Neurofibromatosis type 2(NF2)is a hereditary tumor syndrome characterized by bilateral acoustic nerve tumors, multiple schwannomas, and multiple meningiomas. About half of the patients develop familial onset through an autosomal dominant mode of inheritance. The causative gene of NF2 is the NF2 gene, and those who have a germline mutation of the said gene invariably develop the disease. On the other hand, about half of NF2 patients are sporadic cases. It is thought that the somatic mosaic of the NF2 gene is involved in most of the sporadic cases, in which germline mutation of NF2 is not detected. It is becoming clear that the clinical features, such as the life and functional prognoses of NF2 patients, differ depending on the genotype of the causative gene.

Recent studies have demonstrated that cancer-specific metabolism plays a crucial role in a variety of malignancies, including acute myeloid leukemia (AML). To identify a novel therapeutic target for AML, we conducted a metabolite screen on AML cells and normal hematopoietic stem/progenitor cells (HSPCs) and detected that the metabolism of glycerol-3-phosphate (G3P) is reprogrammed in AML. Glycerol-3-phosphate acyltransferases (GPATs), the first and rate-limiting enzymes in the lipid biosynthesis pathway, convert G3P into lysophosphatidic acid (LPA). Among various GPAT isozymes, GPAT1 was highly expressed in AML cells and silencing it inhibited the cell growth of AML. GPAT1 is located on the outer membrane of the mitochondria and regulates mitochondrial fusion and oxidative phosphorylation (OXPHOS). Silencing GPAT1 promoted mitochondrial fission and reduced OXPHOS. In AML, the GPAT1 inhibitor also suppressed cell proliferation and mitochondrial metabolism. However, this inhibitor had no effect on normal hematopoiesis in vivo. In conclusion, these findings indicate that targeting GPAT1 may be a promising therapeutic strategy for AML, since it suppresses leukemia-specific metabolism without impairing normal HSPCs.

The standard treatment for glioblastoma is maximal surgical resection followed by postoperative temozolomide administration combined with radiation therapy. Although treatment outcomes have improved in recent years, glioblastoma remains a fatal malignant brain tumor. In addition to standard treatment, it is important to understand the characteristics of additional therapies or limited therapeutic modalities, such as bevacizumab, photodynamic therapy, BCNU wafers, tumor treating fields, and genomic medicine. Furthermore, combination therapy should be applied, depending on the individual patient's condition, to treat this intractable disease.

To train medical staffs capable of practicing precision cancer medicine, The University of Tokyo and 5 universities in the Kanto area planned the education program consisting of a variety of scientific fields including genomic science and have offered educational opportunities to graduate school students. The program aiming to facilitate students' knowledge and practical skills in this field is closely connected with the expert panel of cancer genomic medicine in which multidisciplinary medical staffs discuss novel therapeutic choices based on patients' genomic information in the incurable cases lacking standard treatments. Education programs focusing on the treatment of rare cancers as well as childhood and adolescent cancers are also based on multidisciplinary collaborations. In addition to individual programs unique to each university, frequent seminars promote educational collaborations among universities. The expert panels of cancer genomic medicine play a critical role in the finding of subjects suitable for the education of medical staffs in seminars or lectures. Consequently, we established the educational system that is able to maintain practical clinical oncology at a prominent level by introducing multidisciplinary collaboration in precision medicine.

Genes that regulate immunological activities are transiently suppressed by epigenetic modification during the germinal center reaction of B cells and reactivated when B cells exit the germinal center. Mutations of EZH2 and other epigenetic modifier genes are frequently involved in the pathogenesis of follicular lymphoma and lead to silencing of the genes necessary for exiting the germinal center. Tazemetostat, an EZH2 inhibitor, has been approved for the treatment of follicular lymphoma with EZH2 gain-of-function mutations in Japan. Tazemetostat restores the expressions of MHC and CD58 in lymphoma cells and synergistically enhances the immune reactions of T and natural killer cells against lymphoma cells. Tazemetostat also induces lymphoma cells to secrete CCL17/TARC and enhances T-cell migration. CD58 and CCL17 are known to play central roles in the formation of T-cell-rich tumor microenvironment of Hodgkin lymphoma. We found that tazemetostat enhances the expression of genes overexpressed in Hodgkin/Reed-Sternberg cells. Epigenetic modifiers and new molecular targeted therapies are expected to provide new insights into the pathogenesis of lymphoma and mechanisms determining the histology of lymphoma.

Gene panel test, which has been used in the field of solid tumors, is expected to be introduced in the field of hematopoietic tumors in the near future. Unintended germline variants may be detected due to the comprehensive nature of the gene panel test, and these are called "secondary findings." Additionally, it sometimes reveals that a person has germline variants that predispose the carriers to develop the disease. There are several impeding issues to be addressed regarding these germline variants, including detection methods, obtaining informed consent, scope of variants to be disclosed, and genetic counseling methods. In the field of hematopoietic tumors, the problem is further complicated by the possibility of detecting germline variants in donors because allogeneic hematopoietic stem cell transplantation constitutes an important treatment modality in this field. Thus, this paper aims to outline the issues related to germline variants in gene panel tests, which were discussed at the symposium "NGS-based multi-gene panel testing in hematology/oncology" at the annual meeting of the Japanese Society of Hematology in 2021.

Next-generation sequencing (NGS)-based multigene panel testing enables assessment of the mutational status of a few hundred genes associated with cancer pathogenesis. Although such tests have been approved by the Pharmaceuticals and Medical Devices Agency for use in patients with treatment-refractory solid tumors,there are no currently available tests for hematologic malignancies. The resultant information from these panel tests is primarily used to identify a potential treatment regimen or targeted therapy for solid tumors. However, genome profiling in hematologic malignancies also guides the clinical management of patients by providing diagnostic and prognostic information. This review summarizes the potential advantage of NGS-based multigene panel tests over conventional tests to determine therapeutic strategies for hematologic malignancies.

Diagnosis and classification of hematological diseases have been based on morphological and immunological findings, but the emergence of next-generation sequencing (NGS) technology has highlighted the importance of genomic alterations. With the advent of this novel technology, numerous genetic alterations have been identified in hematological malignancies. In fact, more than 300 genetic alterations have been listed in the latest WHO classification, such as NPM1 mutation, for the subcategorization of acute myeloid leukemia. In addition, increasing evidence has suggested that combining genetic information with clinical factors improves prognostic prediction in several hematological malignancies. Although NGS-based genomic profiling has been used to provide precision medicine in solid cancers, no comprehensive genomic profiling test for hematological diseases is covered by public health insurance both in Japan and abroad. Identification of targetable alterations is the main purpose of NGS-based genomic profiling in solid cancers, whereas genetic information is useful not only for treatment stratification but also for diagnosis and prognostic prediction. In addition, genetic profiles of solid and hematological malignancies are quite different. Therefore, the development of a comprehensive genomic profiling test for hematological disease is imperative. Here, we discuss the clinical utility of a comprehensive genomic profiling test for hematological malignancies with an emphasis on diagnosis and prognostic prediction.

This case was a 73-year-old woman who previously underwent a partial colectomy for ascending colon cancer at the age of 70. She had a history of cancer of the uterus, descending colon, bladder, and left ureter. She had a family history of colorectal cancer and met the Amsterdam Ⅱ criteria for Lynch syndrome. She was diagnosed as Lynch syndrome with a MSH2 germline mutation by genetic analysis. One year later, a partial colectomy was performed for sigmoid colon cancer. Six months later, colonofiberscopy revealed early-stage cancer in the rectum, and EMR was performed. Despite adequate surveillance, she had frequent recurrences of advanced colorectal cancer within a short period of time. We report here risk factors of colorectal cancer in Lynch syndrome and indications for prophylactic total colectomy.

Concomitant pancreatic ductal adenocarcinoma (PDA) is observed in a subset of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and early detection of those progressing lesions is difficult. We present a case with a de novo carcinoma in situ (CIS) discovered incidentally around the resection margin of IPMNs. A man in his 70s with a history of acute pancreatitis at the age of 50 years and no family history of PDA had a pancreatoduodenectomy for three isolated branch duct IPMNs that caused recurrent pancreatitis. During the 2-year follow-up period, the index lesion in the pancreatic head grew significantly, whereas the other cysts remained small and without mural nodules. The majority of the cysts are histologically composed of low-grade dysplasia and are classified as gastric-type IPMN. CIS with nuclear overexpression of p53 was located in the main pancreatic duct and adjacent brunch duct, which involved the pancreatic resection margin. The precise pathological analysis combined with multiregion sequencing revealed the CIS harbored KRAS G12V and TP53 R248W. Conversely, IPMNs contained GNAS mutant cells as well as components containing additional KRAS mutations. These findings suggested that the CIS formed independently of the multiple IPMNs and appeared to be an early manifestation of concomitant PDA with coexisting IPMNs. Despite widespread agreement on the resection of the radiographically significant IPMN lesion (s), the latent invasive cancer was not eradicated. A detailed pathological and molecular assessment of the resected materials may aid in a better management strategy for concurrent lesions.

Various reports have been published in recent years on the effects of histone deacetylase (HDAC) inhibitors on programmed death ligand 1 (PD-L1) expression in cancer cells. The combination therapy of immune checkpoint inhibitors and HDAC inhibitors utilizing these effects has attracted attention as a new clinical treatment of triple-negative breast cancers. We investigated how the expression level of PD-L1 changes depending on the type of HDAC inhibitor exposed to triple-negative breast cancer cell line MDA-MB-231. We found that the mRNA expression level of PD-L1 was significantly decreased by Vorinostat and K-32 (pan-HDAC inhibitors) at high concentrations exhibiting low cell viability, while it was increased by high concentrations of K-560 (HDAC1,2 inhibitor) and Entinostat (HDAC1,3 inhibitor). On the other hand, the mRNA level of PD-L1 was increased by all of these HDAC inhibitors at low concentrations showing high cell viability. Of particular note, K-32 induced more PD-L1 mRNA than all the other HDAC inhibitors at the lowest concentration of 0.5 μM. This finding might suggest the usefulness of pan-HDAC inhibitors in clinical treatment in combination with immune checkpoint inhibitors.