Epidermalgrowth factor receptor tyrosine kinase inhibitor(EGFR-TKI)is the first choice for the treatment of EGFR mutation- positive advanced non-small cell lung cancer(NSCLC). There have been few reports on the efficacy and safety of gefitinib in elderly patients with EGFR mutation-positive advanced NSCLC. We retrospectively assessed the efficacy and safety of gefitinib as first-line chemotherapy in 22 patients with advanced NSCLC aged 75 years or older and who were treated with gefitinib. The response rate was 81.8%, and the disease controlrate was 95.5%. The median progression-free survivaltime was 14.2 months, and the median survivaltime was 30.7 months. The common adverse events were skin toxicities(50.0%), liver dysfunction(18.2%), and diarrhea(18.2%). The dose of gefitinib was reduced in 36.3% of the patients, and the treatment of gefitinib was discontinued in 18.2% of the patients. Gefitinib is effective and safe for elderly patients with advanced NSCLC.

A 78-year-old man was admitted with diarrhea. Colonoscopy and computed tomography(CT)revealed rectal cancer with multiple liver metastases. Low anterior resection was performed for local control. After the operation, 5 courses of mFOLFOX6 plus bevacizumab chemotherapy were administered as first-line systemic therapy, but CT showed progressive disease with liver metastases. After the first-line systemic therapy, 2 courses of FOLFIRI plus bevacizumab chemotherapy were performed as second-line systemic therapy, but CT also revealed progressive disease with liver metastases. We retrospectively performed comprehensive genomic sequencing with a 415-gene panel and found that the patient had a hypermutation subtype. Interestingly, the panel also revealed that he had mismatch-repair(MMR)deficiency with MSH2 mutation, which is reported as a possible cause of resistance to 5-fluorouracil in colorectal cancer.

A 74-year-old woman with cT4aN2M0, cStage ⅢB gastric cancer underwent neoadjuvant chemotherapy comprising 2 courses of S-1 plus cisplatin, and the clinical response was determined as non-CR/non-PD according to RECIST ver 1.1. Although distal gastrectomy with D2 lymphadenectomy was planned, the tumor was considered as unresectable with peritoneal metastases during laparotomy. After the subsequent chemotherapy with 1 course of capecitabine plus cisplatin, tumor bleeding, and obstruction due to rapid tumor progression occurred. We performed palliative distal gastrectomy; however, the patient died 17 days after gastrectomy. A comprehensive genomic analysis using cancer-gene panel identified the tumor as a microsatellite instability-high(MSI-H). Recently post hoc analysis of the large-scale clinical trials showed no clinical benefit of perioperative chemotherapy in MSI-H gastric cancer. MSI status has a potential to optimize the perioperative treatment strategy in gastric cancer.

A 43-year-old woman underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometrioid adenocarcinoma of the uterine body(Stage ⅢC)at 40 years of age. Screening of the adenocarcinoma samples for Lynch syndrome by immunohistochemistry for mismatch repair proteins indicated a loss of MSH2/MSH6 proteinexpression . A genetic test revealed a deletion of about 20 kb, including exons 8 and 9 of the EPCAM gene. Colonoscopy revealed a type 1 tumor in the cecum. The risk of developing metachronous colorectal cancer and postoperative survival according to the extent of colectomy(total colectomy versus segmental colectomy)and her marked obesity were considered collectively. The patient subsequently selected total colectomy with ileorectal anastomosis. Pathological findings revealed mucinous carcinoma(Stage Ⅱ). Patients with Lynch syndrome caused by deletion of EPCAM are not usually at a high risk of uterine body cancer, but the risk of developing uterine body cancer should be noted when the range of EPCAM deletion extends near to MSH2, as inthis case.

Subtype classification of breast cancer by analyzing the gene expression profile of cancer cells is becoming a standard procedure. Breast cancer subtype classification is more useful than the conventional method because the characteristics of subtype classification is directly connected with the treatment method. However, genetic testing is invasive, and a part of cancer cells may not represent the overall nature of the cancer. In the computer-aided diagnosis (CAD) scheme for differentiation of triple-negative breast cancer (TNBC) by estimating the genetic properties of cancer based on Radiogenomics, principal component analysis (PCA) and least absolute shrinkage and selection operator (Lasso) were used for reducing the dimension of radiomic features, and we compared usefulness of both. We collected 81 magnetic resonance (MR) images, which included 30 TNBC and 51 others, from the public database. From the MR slice images, we selected the slice containing the largest area of the cancer and manually marked the cancer region. We subsequently calculated 294 radiomic features in the cancer region, and reduced the dimension of radiomic features. Finally, linear discriminant analysis, with the dimensionally compressed 10 image features, was used for distinguishing between TNBC and others. Area under the curve (AUC) was 0.60 when we used PCA, whereas AUC was 0.70 when we used Lasso (p=0.0058). Therefore, Lasso is useful for the determination of radiomic features in Radiogenomics.

Cancer is a very complex disease that is caused by mutations in genomes and evolves spatiotemporally in a patient. Our institute implemented IBM Watson for Genomics and realized a turnaround time for patient diagnosis of less than four days that includes whole genome sequencing and interpretation of the data.

Persistent infection with oncogenic human papillomaviruses (HPVs) is necessary for the development of cervical cancer, although the accumulation of somatic mutations in the host genome is also required for the generation of invasive cervical cancer. Recent studies have demonstrated concomitant genetic changes in the HPV genome; however, their relevance to cervical carcinogenesis is poorly understood. Here we review our recent study investigating the within-host genetic diversity of HPV and its relationship with cervical cancer progression through deep sequencing analyses of viral whole-genome sequences in clinical specimens. Intriguingly, HPV genomes within individual clinical samples show an astonishingly high level of nucleotide variation across all histological grades of cervical lesions. Among the various substitution patterns, C-to-T and C-to-A substitutions are the predominant changes observed in the HPV genomes. Analysis of the trinucleotide context for substituted bases reveals that TpCpN (N is any nucleotide), which is a preferred target sequence for the cellular apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) proteins, is the major target for C-to-T substitutions in the HPV genomes. These mutational signature analyses strongly imply that within-host HPV variations are mostly generated through APOBEC-mediated mutagenesis. Because the HPV oncogenes E6 and E7 harbor APOBEC-related mutations, we propose a potential role for APOBEC-mediated mutagenesis in cervical carcinogenesis.

Resistance to the breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor (TKI), imatinib, poses a major problem in the treatment of chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, the basis of this BCR-ABL1-independent resistance in the absence of such mutation remains to be elucidated. The aim of the present study is to identify the mechanism of imatinib resistance in CML. To gain insight into BCR-ABL1-independent imatinib resistance mechanisms, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, focusing on the receptor tyrosine kinase MET. Treatment with an MET inhibitor resensitized K562/IR cells to BCR-ABL TKIs. A treatment combining imatinib and a MET inhibitor in K562/IR cells inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Moreover, the combination of MET inhibitor and imatinib suppressed tumor growth in vivo. These results indicate that the activation of MET/ERK and MET/JNK are potential mechanisms of BCR-ABL TKI resistance. Our findings provide new and important information concerning the mechanisms of imatinib resistance in CML, and reveal new proteins potentially involved in BCR-ABL TKI resistance.

MSI-H tumors are drove with molecular mechanism different from ordinary carcinoma, and thus the morphological features could be distinct. Particularly, MSI-H colorectal carcinoma has peculiar morphological characteristics, which are listed as one of the criteria to recommend MSI-testing. In this article, morphological characteristics and immunohistological detection of MSI-H colorectal cancer are reviewed, with contrasting to those of gynecological tumors.

Among gynecological cancers, microsatellite instability(MSI)is most commonly found in endometrial carcinoma. When an allelic variation is observed in multiple microsatellite regions, it is called MSI-high(MSI-H). Hereditary MSI-H endometrial cancer develops through a germline mutation ofthe mismatch repair(MMR)gene, resulting in Lynch syndrome, and increased risk ofsporadic MSI-H endometrial cancer is caused by somatic lineage mutations or methylation abnormalities. Clinical characteristics ofendometrial cancer involved in Lynch syndrome include symptoms such as onset at a younger age, a lower corpus segment at the site, earlier stage cancer, and varied histology, when compared with those ofthe sporadic cancer. Alternatively, somatic mutations ofthe MMR gene are highly heterogeneous; however, a meta-analysis showed no difference in prognosis between with and without MSI-H. MSI-H is considered to be a biomarker, showing the therapeutic effects of an immune checkpoint inhibitor. A recent randomized controlled trial(RCT)demonstrated that an immune checkpoint inhibitor was effective against colorectal cancer with MSI-H. An additional RCT proved its effectiveness for MSI-H solid cancers, regardless oforgan type, including endometrial cancer. As the number ofcases ofendometrial cancer is increasing in Japan, MSI-H may hold utility as a biomarker for new molecular-target drugs, including immune checkpoint inhibitors. Ongoing surveillance ofcarcinomas in patients and family members is important because endometrial carcinoma associated with Lynch syndrome is a hereditary tumor. However, there is currently no established surveillance method for endometrial cancer. To improve the overall prognosis ofpatients with Lynch syndrome, genetic counseling and cross-division management are necessary, and also establishing the system is urgently required.

In May 2017, the Food and DrugAdministration granted accelerated approval to pembrolizumab for microsatellite instability- high(MSI-H)or deficient mismatch repair(dMMR)solid tumors irrespective to tumor origins. Lynch syndrome is one of the diseases causingMSI -H tumor, however some sporadic cancers have MSI-H. We focus on the frequency of Lynch syndrome and sporadic MSI-H tumor in urological cancer.

In recent years, immunotherapy has shown promising results in various types of cancers. Checkpoint inhibitor drugs developed for cancer immunotherapy have been approved by the US Food and Drug Administration(FDA)for adult patients with microsatellite instability-high(MSI-high)or mismatch repair deficient(dMMR)solid tumors. In addition, FDA approves nivolumabfor MSI-high or dMMR colorectal cancer. MSI status has an important role in colorectal cancer management.

Genome medicine has been attractingmuch of attention in Japan. The combination of molecular targetingdrug s and somatic mutations has been developed for cancer treatment, which was introduced clinically with evidence by cancer type. Several cancer somatic mutations can be identified in a single test inexpensively using next-generation sequencing(NGS). Drug approval not based on organs but on cancer genome analysis has been practiced mainly in the United States, and is also being implemented in Japan. However, cancer treatment strategies using molecular targeting drugs and the associated diagnosis are limited in each type of cancer. Furthermore, the benefit of NGS, which is an improved and inexpensive technique, is still insignificant in Japan. However, the clinical biobank system was initiated in 2011 to prepare the era of cancer genome medicine in our department. The quality of biological samples was strictly controlled by the standardized sampling procedures, which can be used by the researchers accordingto their convenience. Furthermore, the cooperative research involvingcommercial corporations has been started.

Recent research reveals novel insights into the pathogenesis of childhood myelodysplastic syndromes (MDS) in addition to that of juvenile myelomonocytic leukemia (JMML). In pediatric MDS, the genetic characteristics of which have been barely elucidated previously, germline mutations, particularly those in GATA2, SAMD9, and SAML9L, have been frequently identified, indicating the importance of germline predisposition in childhood MDS compared with adult MDS. In JMML, in addition to the known Ras-pathway mutations, novel secondary mutations and causative fusion genes have been reported. This review aims to summarize the recent progress in the research of the pathogenesis of childhood MDS and JMML.