Next‐generation sequencing ( NGS ) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital‐based prospective study ( TOP ‐ GEAR project, 2nd stage) to investigate the feasibility and utility of NGS ‐based analysis of 114 cancer‐associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer‐related societies. Twenty‐five (13.3%) cases have since received molecular‐targeted therapy according to their gene aberrations. These results indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry ( UMIN 000011141).

The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer.

No abstract

Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed <40 years to 3.2% in patients ≥80 years, with BRCA1/2, explaining two-thirds of pathogenic variants identified at all ages. BRCA1/2, PALB2, and TP53 are significant causative genes. Patients with pathogenic variants in BRCA1/2 or PTEN have significantly younger age at diagnosis. In conclusion, BRCA1/2, PALB2, and TP53 are the major hereditary breast cancer genes, irrespective of age at diagnosis, in Japanese women.

Urothelial cancer (UC) develops along two different genetic pathways, resulting in noninvasive or invasive tumors. However, it is unknown whether there are also different epigenetic pathways in UC. UC is also characterized by a high rate of recurrence, and the presence of a field defect has been postulated. In this study, we compared the DNA methylation patterns between noninvasive and invasive UC and the DNA methylation patterns between normal-appearing urothelium from bladders with cancer and urothelium from cancer-free bladders. We used the Illumina GoldenGate methylation assay at 1,370 loci in 49 noninvasive urothelial tumors, 38 invasive tumors with matched normal-appearing urothelium, and urothelium from 12 age-matched UC-free patients. We found distinct patterns of hypomethylation in the noninvasive tumors and widespread hypermethylation in the invasive tumors, confirming that the two pathways differ epigenetically in addition to genetically. We also found that 12% of the loci were hypermethylated in apparently normal urothelium from bladders with cancer, indicating an epigenetic field defect. X-chromosome inactivation analysis indicated that this field defect did not result in clonal expansion but occurred independently across the urothelium of bladders with cancer. The hypomethylation present in noninvasive tumors may counterintuitively provide a biological explanation for the failure of these tumors to become invasive. In addition, an epithelium-wide epigenetic defect in bladders with cancer might contribute to a loss of epithelial integrity and create a permissible environment for tumors to arise. Cancer Res; 70(20); 8169-78. ©2010 AACR.

lthough gastric carcinoma has recently shown a gradual decrease in prevalence, it still accounts for a significant proportion of cancer-related deaths in Japan. To improve the cure rate, more attention should be directed to early detection and prevention of metastasis of this cancer. Scirrhous carcinoma of the stomach, known as diffusely infiltrative carcinoma or Borrmann's type-IV carcinoma, or linitis plastica-type carcinoma, is characterized clinically as having the worst prognosis among the various types of gastric cancer, because it is frequently associated with metastases to lymph nodes and peritoneal dissemination. However, the mechanisms underlying this propensity for metastasis are not yet clearly understood. Therefore, establishment of relevant animal models of metastasis is considered to be extremely important for the elucidation of these mechanisms and establishment of appropriate therapeutic approaches. Transplants of human tumors into nude mice have been used increasingly as experimental systems for this purpose.1) Many human tumors can proliferate when injected s.c. into nude mice, but metastasis from the site of injection is rare.2) It has been found that in most models of human cancers, including gastric carcinoma, i.v. or intrasplenic injection, or orthotopic implantation of the tumor cells is necessary to generate metastasis. [3][4][5][6] There are few reports of spontaneous metastasis from human gastric tumor xenografts in nude mice. 7,8) To date, only one experimental model of signet-ring cell or scirrhous carcinoma of the stomach has been reported. 9) In order to address this problem, we previously established and characterized four cell lines from a primary gastric carcinoma and disseminated metastatic lesions of gastric scirrhous carcinoma.10-12) These cell lines did not exhibit the potential to form experimental or spontaneous metastases when injected s.c. or i.v., or implanted orthotopically into nude mice.We now report the establishment and the biological characterization of new human signet-ring cell gastric carcinoma cell lines that exhibit the ability to metastasize spontaneously in nude mice. Materials and MethodsOrigin and establishment of the cell lines. The HSC-44PE cell line was established from the pleural fluid, obtained by thoracocentesis, of a 28-year-old female Japanese patient with scirrhous gastric carcinoma (linitis plastica-type). The previously reported 12) and the HSC-44PE cells reported in this paper, were derived from the same patient. The former was derived from the ascitic fluid in the early stage of scirrhous gastric carcinoma, while the latter was established by culture of tumor cells collected from the pleural fluid in the terminal stage of the cancer. The HSC-58 cell line was established from the ascitic fluid, obtained by peritoneocentesis, of a 57-year-old male Japanese patient with scirrhous gastric carcinoma. The HSC-60 cell line was established from the ascitic fluid, obtained by peritoneocentesis, of a 40-year-old male patient with scirrhous gastric car...

Multiple endocrine neoplasia (MEN) type 2B is a clinically distinct entity among the autosomal dominant MEN 2 syndromes. Most patients with MEN 2B carry a germline mutation (M918T) of the RET proto‐oncogene, while a few carry A883F. We examined a patient with MEN 2B, but without M918T or A883F, and her relatives. Here, we report the presence in this patient of 2 germline mutations, V804M and Y806C in the same allele. While the novel Y806C was inherited from her father, its carriers (her father and brother) was not affected by MEN 2. In contrast, V804M was a de novo mutation, that has been reported in patients with familial medullary thyroid carcinoma. Combinations of mutations of the RET proto‐oncogene may cause oncogenic activities different from those of single mutations.

Background Genetic testing has been conducted in patients with prostate cancer (PCa) using multigene panels, but no centralized guidelines for genetic testing exist. To overcome this limitation, we investigated the demographic and clinical characteristics of patients with pathogenic variants. Methods We sequenced eight genes associated with hereditary PCa in 7636 unselected Japanese patients with PCa and 12 366 male, cancer-free control individuals. We assigned clinical significance for all 1456 variants using the American College of Medical Genetics and Genomics guidelines and ClinVar. We compared the frequency of carriers bearing pathogenic variants between cases and control participants with calculated PCa risk in each gene and documented the demographic and clinical characteristics of patients bearing pathogenic variants. All statistical tests were two-sided. Results We identified 136 pathogenic variants, and 2.9% of patients and 0.8% of control individuals had a pathogenic variant. Association with PCa risk was statistically significant for variants in BRCA2 (P &lt; .001, odds ratio [OR] = 5.65, 95% confidence interval [CI] = 3.55 to 9.32), HOXB13 (P &lt; .001, OR = 4.73, 95% CI = 2.84 to 8.19), and ATM (P &lt; .001, OR = 2.86, 95% CI = 1.63 to 5.15). We detected recurrent new pathogenic variants such as p.Gly132Glu of HOXB13. Patients with pathogenic variants were 2.0 years younger at diagnosis and more often had smoking and alcohol drinking histories as well as family histories of breast, pancreatic, lung, and liver cancers. Conclusions This largest sequencing study of PCa heredity provides additional evidence supporting the latest consensus among clinicians for developing genetic testing guidelines for PCa.