Colon cancer has been viewed as the result of progressive accumulation of genetic and epigenetic abnormalities. However, this view does not fully reflect the molecular heterogeneity of the disease. We have analyzed both genetic (mutations of BRAF, KRAS, and p53 and microsatellite instability) and epigenetic alterations (DNA methylation of 27 CpG island promoter regions) in 97 primary colorectal cancer patients. Two clustering analyses on the basis of either epigenetic profiling or a combination of genetic and epigenetic profiling were performed to identify subclasses with distinct molecular signatures. Unsupervised hierarchical clustering of the DNA methylation data identified three distinct groups of colon cancers named CpG island methylator phenotype (CIMP) 1, CIMP2, and CIMP negative. Genetically, these three groups correspond to very distinct profiles. CIMP1 are characterized by MSI (80%) and BRAF mutations (53%) and rare KRAS and p53 mutations (16% and 11%, respectively). CIMP2 is associated with 92% KRAS mutations and rare MSI, BRAF, or p53 mutations (0, 4, and 31% respectively). CIMP-negative cases have a high rate of p53 mutations (71%) and lower rates of MSI (12%) or mutations of BRAF (2%) or KRAS (33%). Clustering based on both genetic and epigenetic parameters also identifies three distinct (and homogeneous) groups that largely overlap with the previous classification. The three groups are independent of age, gender, or stage, but CIMP1 and 2 are more common in proximal tumors. Together, our integrated genetic and epigenetic analysis reveals that colon cancers correspond to three molecularly distinct subclasses of disease.classification ͉ DNA methylation ͉ genetic alterations C olorectal cancer (CRC) is the second and fourth most common cancer in men and women, respectively (1). Approximately 70% of colorectal cancers are sporadic, with no inherited predisposition. A stepwise progression model involving two distinct genetic pathways has been proposed to explain the etiology of colon cancer from benign neoplasm to adenocarcinoma (2). One class of genetic alterations involves mutations of oncogenes and tumor-suppressor genes that directly control cell birth and death, such as APC, KRAS, and p53. Another involves mutations of DNA mismatch repair genes.In addition to these genetic alterations, cancer initiation and promotion can occur by epigenetic mechanisms (3). CpG methylation is the best characterized epigenetic change in the mammalian genome. Whereas CpG dinucleotides are underrepresented in the mammalian genome, approximately half of all human genes contain a CpG-rich region called a ''CpG island'' in the 5Ј area, often encompassing the promoter and transcription start site of the associated gene (4, 5). Gene silencing by hypermethylation of CpG islands (including tumor-suppressor genes) is a common event in tumors. Further, hypermethylation of specific genes such as ER␣, MYOD1, and N33 occurs in the normal colon tissue of aging individuals (6, 7), and hypermethylation of the secreted frizzled-relat...
We retrospectively investigated the efficacy and feasibility of concurrent chemoradiotherapy for patients with severe dysphagia caused by oesophageal squamous cell carcinoma. Concurrent chemoradiotherapy was performed in 57 patients with T3 or T4 disease containing M1 lymph node (LYM) disease. Chemotherapy consisted of protracted infusion of 5-fluorouracil (5-FU) 400 mg m À2 24 h À1 on days 1 -5 and 8 -12, combined with 2-h infusion of cisplatin (CDDP) 40 mg m À2 on days 1 and 8. Radiation treatment at a dose of 30 Gy in 15 fractions of the mediastinum was administered concomitantly with chemotherapy. A course schedule with 3-week treatment and a 1 to 2-week break was applied twice, with a total radiation dose of 60 Gy, followed by two or more courses of 5-FU and CDDP. In all, 24 patients (42%) achieved a complete response, and the 3-year survival rate was 19%. Major toxicities were leukocytopenia and oesophagitis, and there were two (4%) treatment-related deaths. In contrast, 22 patients with T3 disease survived longer than 35 patients with T4 disease (P ¼ 0.001); however, the survival rate in 15 patients with M1 LYM disease did not differ significantly from that in 42 patients without M1 LYM disease (P ¼ 0.3545). Our results indicate that definitive chemoradiotherapy is potentially curative for locally advanced oesophageal carcinoma with malignant stricture. The efficacy and survival of patients treated with this regimen are related to the T factor.
Ga2O3 field-plated Schottky barrier diodes (FP-SBDs) were fabricated on a Si-doped n−-Ga2O3 drift layer grown by halide vapor phase epitaxy on a Sn-doped n+-Ga2O3 (001) substrate. The specific on-resistance of the Ga2O3 FP-SBD was estimated to be 5.1 mΩ·cm2. Successful field-plate engineering resulted in a high breakdown voltage of 1076 V. A larger-than-expected effective barrier height of 1.46 eV, which was extracted from the temperature-dependent current–voltage characteristics, could be caused by the effect of fluorine atoms delivered in a hydrofluoric acid solution process.
We investigated the temperature-dependent electrical properties of Pt/Ga2O3 Schottky barrier diodes (SBDs) fabricated on n–-Ga2O3 drift layers grown on single-crystal n+-Ga2O3 (001) substrates by halide vapor phase epitaxy. In an operating temperature range from 21 °C to 200 °C, the Pt/Ga2O3 (001) Schottky contact exhibited a zero-bias barrier height of 1.09–1.15 eV with a constant near-unity ideality factor. The current–voltage characteristics of the SBDs were well-modeled by thermionic emission in the forward regime and thermionic field emission in the reverse regime over the entire temperature range.
Aberrant promoter hypermethylation and associated gene silencing are epigenetic hallmarks of tumorigenesis. It has been suggested that aberrant DNA methylation can affect the sensitivity of cancers to antineoplastic agents by altering expression of genes critical to drug response. To study this issue, we used bisulfite PCR to assess DNA methylation of 32 promoter-associated CpG islands in human cancer cell lines from the National Cancer Institute (NCI) drug-screening panel (NCI-60 panel). The frequency of aberrant hypermethylation of these islands ranged from 2% to 81% in NCI-60 cancer cells, and provided a database that can be analyzed for the sensitivity to %30,000 drugs tested in this panel. By correlating drug activity with DNA methylation, we identified a list of methylation markers that predict sensitivity to chemotherapeutic drugs. Among them, hypermethylation of the p53 homologue p73 and associated gene silencing was strongly correlated with sensitivity to alkylating agents. We used small interfering RNA to down-regulate p73 expression in multiple cell lines, including the resistant cell lines TK10 (renal cancer) and SKMEL28 (melanoma). Down-regulating p73 substantially increased sensitivity to commonly used alkylating agents, including cisplatin, indicating that epigenetic silencing of p73 directly modulates drug sensitivity. Our results confirm that epigenetic profiles are useful in identifying molecular mediators for cancer drug sensitivity (pharmaco-epigenomics).
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