Seminal studies by Dr. Shinya Yamanaka revealed that reprogramming technology was able to convert differentiated somatic cells to self-renewing and pluripotent stem cells. Although reprogramming process does not require changes in the genome information, cellular reprogramming elicits dynamic changes of epigenetic regulation. Therefore, reprogramming technology is a powerful tool for the modifying epigenetic regulation. Previous studies have reported that epigenetic regulation plays a critical role on both the development and maintenance of cancer cells. Taking advantage of reprogramming technology, previous studies have actively modified the epigenome of cancer cells and revealed the importance of the coordinated interactions between genetic abnormalities and epigenetic regulation in cancer cells. In this review, we describe advances and challenges in the use of reprogramming technology for studying cancer biology.

A woman in her 30s presented to our hospital with the chief complaint of a right breast mass after the birth of her first child. She was diagnosed as having right invasive ductal carcinoma of Luminal-B type and T3N3cM0, stage Ⅲc. While undergoing neoadjuvant chemotherapy, she received genetic counseling and underwent genetic testing and was determined to have deleterious BRCA1 and BRCA2 mutations. After completing chemotherapy, she underwent a right total mastectomy and axillary lymph node dissection. Two years postoperatively, she requested to undergo a contralateral risk-reducing mastectomy( CRRM)of her left breast. Therefore, CT and breast MRI were performed to confirm the absence of contralateral lesions and distant metastases, and subsequently, CRRM was performed. Postoperative pathology results showed non-invasive ductal carcinoma lesions at 5 sites. In the case of hereditary breast and ovarian cancer syndrome such as in this study, lesions may be discovered at an early stage by performing risk-reducing mastectomy.

Meningioma and glioma represent two common primary intracranial tumors. However, the coexistence of these two lesions in the same patient at the same location is rare. Here, we present a case of a fibroblastic meningioma with a secondary glioblastoma occurring at the same location. A 67-year-old woman underwent surgery for a left frontal parasagittal meningioma, and the tumor was subtotally removed. Two years and 11 months after the surgery, the patient had a tumor at the same location with invasion into the adjacent brain, suggesting recurrent meningioma with malignant transformation. The resected tumor was confirmed histopathologically as a glioblastoma. Genetic analysis revealed that the isocitrate dehydrogenase 1 and 2 genes were wild type, and the TERT promoter mutation was detected. The gene analysis suggests that the tumor was a de novo glioblastoma, not a secondary glioblastoma from a lower-grade glioma. (Received April 9, 2020; Accepted May 27, 2020; Published October 1, 2020).

Owing to recent advances in genome analysis technology, many chromosomal abnormalities and gene mutations involved in leukemia onset or recurrence have been discovered in acute myeloid leukemia. These findings contribute to not only the clinical usage, such as prognostic factors or minimal/measurable residual disease (MRD) markers, but also to the development of novel molecular-targeted drugs. In this study, the utility of MRD analysis using the NPM1 mutation and prognosis analysis using a highly sensitive KIT mutation detection method will be outlined.

This review aimed to evaluate the molecular mechanism underlying the development of myeloproliferative neoplasms (MPN) caused by mutant calreticulin (CALR). This mutation is found in a subset of patients with Philadelphia chromosome-negative MPNs, and it encodes a molecular chaperone. However, it is essentially impossible to elucidate the oncogenic property of mutant CALR from the wild-type CALR function. Studies have reported that mutant CALR forms a homomultimeric complex via intermolecular interaction between novel domains acquired due to a frameshift mutation, gains a high binding affinity for myeloproliferative leukemia protein (MPL), the thrombopoietin receptor, through a presumptive structural change, and acts as an agonist for MPL. In this review, I would like to describe the course of the discovery of this unique molecular mechanism and discuss future scope of research on mutant CALR.

Here, we report about a woman in her 30s who had peritoneal dissemination and multiple colon cancer with high-frequency microsatellite instability(MSI-H). Her father, paternal grandfather, and maternal grandmother had a history of colorectal cancer treatment. Thus, Lynch syndrome was suspected. We performed R0 resection for peritoneal dissemination and subsequent peritoneal dissemination. A 435-gene panel testing using a next-generation sequencer identified MSH2 and other mutations in the tumor. Hence, we speculated that she could have a germline mutation of MSH2, which causes Lynch syndrome. In the future, if she wishes to receive genetic counseling and undergo germline testing for variants to confirm the diagnosis of Lynch syndrome, we will perform them after receiving informed consent.

The RUNX1 gene is a critical transcription factor for the generation and maintenance of hematopoietic stem cells. RUNX1 is also one of the most frequently mutated gene in sporadic leukemias. Heterozygous loss-of-function mutations of the RUNX1 gene in the germline cause a rare autosomal dominant disorder called familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML). Besides the preexisting platelet disorder in FPD/AML patients, AML also develops in 20-60% of affected individuals. Since its discovery by the Gilliland group in 1999, RUNX1 mutation in the germline has been extensively investigated in the field. The past two decades of research have taught us three important lessons: 1) patients with FPD/AML display atypical symptoms and they have a widened clinical spectrum of FPD, such as eczema and syndromic thrombocytopenia, 2) the elucidation of variant of uncertain significance (VUS) of RUNX1 have revealed their role in epigenetic functions and involvement in the Fanconi anemia DNA repair pathway, and 3) non-coding mutations of RUNX1 also causes FPD/AML. In three distinct familial cases, an enhancer for RUNX1, eR1, was either lost or disconnected from the promoter through genetic deletion or chromosomal translocation abnormalities. This experience, with congenital mutations of RUNX1, will be very useful for future research for a series of other leukemia-causing germline mutations that have been recently identified.

In Japan, clinically, a decade has passed since KRAS exon 2 hotspot mutations could be measured as a companion diagnostic agent of an anti-epidermal growth factor receptor antibody to treat unresectable advanced colorectal cancer. Till now, not only KRAS exon 2, but also KRAS exon 3, 4 and NRAS exon 2-4 mutation, and BRAF mutation(V600E)are approved as insurance as a companion diagnostics tool. In addition to those somatic mutations observed in Ras-Raf signal cascade, the measurement of microsatellite instability status is also approved as a companion diagnostic to anti-programmed death-1 receptor antibodies. Since these somatic mutational profiles in colorectal cancer cells are measured to determine the propriety of administration of a particular medicine, the results must be appropriately reflected in therapy for each patient. In this review, I will summarize the feature of clinical characteristics belonging to each somatic mutational profile commonly observed in colorectal cancer, and discuss howsuch somatic mutational profiles including RAS, BRAF mutation, and microsatellite instability status bring us to a newera of colorectal cancer.

Among breast cancer cases, 5-10% are thought to have germline mutations in genes associated with onset. Among these, hereditary breast cancer-ovarian cancer syndrome, which develops from breast cancer susceptibility (BRCA) gene mutation, has become widely known. Since 2018, olaparib has been clinically available for patients with inoperable or recurrent breast cancer. However, to use this medicine, BRCA gene mutation must be confirmed. Our hospital has prepared a BRCA genetic testing procedure, counseling system, and environment for the safe use of olaparib for BRCA genetic mutation positive patients. Until patients get the results of the BRCA gene examination, the attending physician and certified in breast cancer nurse care for the patient. If a positive result is obtained, we have established cooperation with a neighboring hospital, since our hospital cannot provide the genetic counseling. The main role of pharmacists is to develop a description system, as with other therapeutic agents, and to develop measures to help with supportive care for side effects. Also important is the development of a system to provide information to community pharmacies. At this symposium, we will report on how we developed our treatment strategy for patients with hereditary breast cancer syndrome, and the integrated role of pharmacists at Hamamatsu Medical Center.

We established an outpatient service in November 2017 to provide cancer gene profiling test services to cancer patients. To date, we have seen approximately 100 patients. Our staff includes genetic counselors and nurses specialized in genetic medicine. Our experience highlights the importance of healthcare professionals having in-depth knowledge of cancer therapeutic drugs and/or investigational drugs based on cancer genome medicine. Recently, poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for treating breast cancer patients with germline BRCA mutation; thus, in-depth knowledge of genetics and skills for genetic counseling are often considered indispensable in working with cancer patients. However, because the prompt treatment of clear and present cancer is the top priority in clinical settings, providing genetic information at that time, including that of unaffected family members, is of low priority for most patients who are dealing with the severe side effects of anti-cancer therapies. Pharmacists have an essential role to play in cancer therapeutics, talking with patients in order to assess their condition and to clarify the status of their treatment with anticancer agents. Genetic pharmacists should therefore work closely with genetics nurses and genetic counselors in the clinical practice of cancer genomic medicine. In this symposium, I would like to describe our experience caring for patients through our outpatient service, and to discuss the ideal framework for multidisciplinary cooperation to promote cancer genomic medicine.

The development of cancer genomic medicine has been embraced as an important new policy issue in "The 3rd Basic Plan to Promote Cancer Control Programs" formulated by the Japanese government. Cancer-associated gene panel testing has been recognized by the public health insurance system since July 2019, and is a critical component of the clinical implementation of genomic science. Because of this dynamic change in cancer medicine, pharmacists are now expected to acquire knowledge about genomic science, and to apply it to individualized and appropriate pharmacotherapies. This review outlines the roles of pharmacists in cancer genomic medicine.

The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.

Advances in genomic medicine have enabled the development of precise cancer therapies (precision cancer medicine) through multigene testing. Toward this end, we have developed a novel clinical sequencing system called PleSSision (Pathologist edited, Mitsubishi Space Software supervised clinical sequence system for personalized medicine) that performs amplicon exome sequencing targeting 160 cancer genes. Using this system, we have examined more than 600 cases over 3 years, and have identified druggable gene alteration in approximately 60% of the cases. Performing such clinical sequencing requires management of the sample quality and sequencing by pathologists and laboratory technicians; bioinformatics analysis by biomedical scientists; and patient care by nurses and pharmacists, all based on specific skills and knowledge of genomics. In addition, patients diagnosed with a hereditary cancer syndrome based on clinical sequencing results must receive care from a genetic counselor and a medical doctor with expertise in genetics. Recently, poly(ADP-ribose)polymerase (PARP) inhibitors and immune checkpoint inhibitors have been used in the treatment of patients with hereditary cancer syndromes, so collaboration involving other medical staff, especially genomic pharmacists, is also required. In this session, we provide an overview of cancer genomic medicine and emphasize the role that genomic pharmacists play in cancer precision medicine.

Recently, mRNAs and microRNAs (miRNAs) have been identified in exosomes, which can be taken up by neighboring or distant cells. These exosomal-miRNAs may regulate gene expression in recipient cells. miRNAs are a type of non-coding RNA that induce post-transcriptional gene silencing of their target genes and regulate a wide range of biological processes, including apoptosis, differentiation, metabolism, and cell proliferation. According to recent reports, aberrant expression of miRNAs is associated with most pathological disease processes, including carcinogenesis. Therefore circulating onco-miRs are considered as significant therapeutic targets for cancer therapy. However, there is no report to regulate the function of miRNAs in exosomes. In this study, we developed novel drug delivery system using anti-exosome antibody-oligonucleotide conjugates (ExomiR-Tracker) for functional inhibition of circulating miRNAs. The "ExomiR-Tracker" is the world's first innovative molecule that has targeting property for exosome-recipient cells and specifically delivers nucleic acid medicines to the target cells. We found that ExomiR-Tracker can bind to the surface of exosomes and that the complexes are introduced into exosome-recipient cells then inhibit the activity of miRNA. We showed that ExomiR-Tracker can accumulate in cancerous tumors after intravenous administration. Existing technologies have difficulties for introducing anti-miR into exosomes and extremely low possibility to deliver anti-miR to exosome-recipient cells after intravenous administration. However, we successfully developed useful inhibition technology against exosomal-miRNA.

Several chromosomal abnormalities and gene mutations involved in the onset and recurrence of acute myeloid leukemia (AML) were discovered with the recent progress of genome analysis technology. The founding not only have clinical application as prognostic factors and minimal residual disease markers but also contribute to the novel molecular-targeted drug development. Many new drugs such as first-generation FLT3 inhibitor, IDH1/2 inhibitor, and BCL2 inhibitor have been developed in Europe and the United States. In addition, second-generation FLT3 inhibitors, gilteritinib and quizartinib, were developed in Japan, and the treatment outcome of AML has been improved. However, a large disparity in the drug availability remains between Europe and the United States and Japan. As a result, treatment guidelines in Europe and the United States cannot be applied to the practical use in Japan. In this paper, molecular-targeted drug treatment by gene diagnosis will be considered for AML in Japan, and the future paradigm shift of gene diagnosis and treatment of AML will be outlined.

A 78-year-old man was hospitalized because of rapid progression of chronic renal failure and diagnosed with multiple myeloma (MM) IgG-λ type ISS-III R-ISS-II with complex karyotype including t(14;19). Even after receiving bortezomib-based regimens, his renal failure progressed. He became dependent on dialysis, which was required three times a week. After introducing the daratumumab (DARA)-based regimen, his renal function improved, the frequency of dialysis decreased to twice a week, and the free light chain (FLC) ratio also improved. However, his myeloma eventually followed a refractory course; therefore, pomalidomide (POM)-dexamethasone (Pd) regimen was administered. Pd regimen had a marked effect and normalized the FLC ratio after three courses of the treatment. However, his myeloma reprogressed with multiple extramedullary masses and he became del(17p) positive; eventually, he died on the 470th day of disease. MM with t(14;19) is rare and has a poor prognosis with a highly aggressive course; however, early introduction of DARA or POM may provide long-term response.

Pembrolizumab and nivolumab are anti-programmed death receptor-1(PD-1)antibodies. The use of pembrolizumab for unresectable or metastatic cancer with microsatellite instability-high(MSI-High)has been recently approved. However, there were few clinical reports on MSI in gastric cancer.