ABSTRACT
Malignant mesothelioma (MM) is a rare disease with a poor prognosis. Pleural mesothelioma, which is the most common type of MM, is considered to be caused by asbestos exposure and is increasing in incidence, with about 15,000 new cases diagnosed worldwide annually. On the other hand, peritoneal mesothelioma is a very rare type of MM; thus, its pathogenesis is even less understood than pleural mesothelioma. Recent research on the pathogenesis of malignant pleural mesothelioma has indicated that both epigenetic and genetic alterations contribute to tumorigenesis. Here, we hypothesize that peritoneal mesothelioma also has an epigenetic alteration in the same genes (Kazal-type serine peptidase inhibitor domain 1 (KAZALD1), transmembrane protein 30B (TMEM30B), and mitogen-activated protein kinase 13 (MAPK13)). Our goal is to identify DNA methylation of these three candidate genes in two peritoneal mesothelioma cases. Laser capture microdissection was used to separate diseased sections of formalin-fixed paraffin-embedded samples from one surgically resected tissue (epithelial type) and one autopsy tissue (sarcomatous type). Genomic DNA was subsequently extracted by the standard phenol chloroform method. The DNA was then treated with sodium bisulphite, and pyrosequencing analysis was used to quantitatively analyze the methylation of candidate genes reported to be hypermethylated in malignant pleural mesothelioma (KAZALD1, TMEM30B, and MAPK13). TMEM30B and MAPK13 were not methylated in either case. However, KAZALD1 was highly methylated in sarcomatoid-type peritoneal mesothelioma. We first report that the KAZALD1 gene was hypermethylated in sarcomatoid-type malignant peritoneal mesothelioma.
Subject(s)
Biomarkers, Tumor/genetics , DNA Methylation , DNA, Neoplasm/genetics , Mesothelioma/genetics , Peritoneal Neoplasms/genetics , Pleural Neoplasms/genetics , Sarcoma/genetics , Adult , Aged , Base Sequence , Biomarkers, Tumor/metabolism , Female , Humans , Immunoenzyme Techniques , Male , Membrane Proteins/genetics , Mesothelioma/pathology , Mesothelioma/surgery , Mitogen-Activated Protein Kinase 13/genetics , Molecular Sequence Data , Mutation/genetics , Peritoneal Neoplasms/pathology , Peritoneal Neoplasms/surgery , Pleural Neoplasms/pathology , Pleural Neoplasms/surgery , Polymerase Chain Reaction , Prognosis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , Sarcoma/pathology , Sarcoma/surgery , Serine Proteinase Inhibitors/genetics , Tumor Suppressor Protein p53/genetics , ras Proteins/geneticsABSTRACT
The pharmacokinetics of irinotecan vary markedly between individuals. This study sought to compare tailored irinotecan and S-1 therapy with S-1 monotherapy for the treatment of patients with advanced/recurrent gastric cancer. Patients with advanced/recurrent gastric cancer were randomized to receive tailored irinotecan and S-1 (arm A) therapy or S-1 therapy alone (arm B). Arm A received S-1 (80-120 mg/m(2)/day) for 14 days, with irinotecan on days 1 and 15. The initial irinotecan dose of 75 mg/m(2) (level 0) was adjusted for toxicity during an earlier course. In arm B, S-1 (80-120 mg/day) was administered alone for 28 days, followed by 14 days without therapy. Ninety-five patients were randomized (48 patients to arm A and 47 patients to arm B). The response rate of the primary tumor (Japanese criteria) was 25.0% in arm A (12 of 48 patients) and 14.9% in arm B (seven of 47 patients), whereas the response rates according to Response Evaluation Criteria In Solid Tumors were 27.8% (10 of 36) versus 21.9% (seven of 32). Hematological toxicity, anorexia, and diarrhea were significantly more common in arm A, but both arms had similar grades 3-4 toxicities. These findings suggest the usefulness of tailored irinotecan and S-1 therapy for gastric cancer.
