Abstract Introduction Gene amplification is an important mechanism for activating oncogenes in malignant tumors. Although amplification of HER2 , C-MYC , CCND1 and FGFR1 has been reported in breast cancers, their role in the progression of in situ to invasive breast carcinoma is unclear. To investigate this question we compared the amplification frequencies of these genes in pure ductal carcinoma in situ (DCIS), DCIS associated with invasive carcinoma, and invasive carcinoma. Methods We performed fluorescence in situ hybridization of the selected genes on tissue microarrays composed of 179 pure DCIS and 438 invasive carcinomas. Two hundred and sixteen of the latter had DCIS components, and in those cases we compared gene amplification in the intraductal and invasive components of each carcinoma. Results The rate of amplification of FGFR1 was higher in invasive carcinomas than in the pure DCIS, but the opposite was true for HER2 amplification. These findings applied consistently to high-grade tumors, but not to low/intermediate-grade tumors. The amplification status of HER2 , C-MYC , CCND1 and FGFR1 was generally similar in the matched invasive and DCIS components of the same tumors. However, FGFR1 amplification was more common in the invasive components than in the DCIS components. In survival analyses, FGFR1 amplification was found to be an independent prognostic factor for poor disease-free survival for all patients with invasive carcinoma and for the hormone receptor-positive subgroup. Conclusion Amplification of HER2 , C-MYC and CCND1 seems to play a role in the early development of breast cancer, but not in its progression. However, the increased frequency of FGFR1 amplification in invasive carcinomas compared with pure DCIS and in the invasive components of individual tumors, and its association with decreased disease-free survival, suggests a role for FGFR1 amplification in the progression of breast cancer including in situ -to-invasive transition, as well as initiation.
The Making of International Law in Korea addresses the development of international law in Korea and Korea’s approach to contemporary international legal issues.
Abstract Aim: To evaluate the clinical significance of intratumoral HER2 heterogeneity in gastric cancer (GC). Methods: A total of 322 GC tissues were evaluated by HER2 immunohistochemistry (IHC), of which 73 with IHC 2+ or 3+ were subjected to fluorescence in situ hybridization (FISH). Also, 3-5 distinct spots in each case showing different HER2 staining intensity were evaluated individually for comparing IHC staining intensity with gene copy number (GCN). Minimum, average, and maximum FISH scores were generated for each case. Results: Intratumoral heterogeneity of HER2 overexpression and gene amplification were 54 and 30 of 73 cases with IHC 2+ or 3+, respectively. These cases were characterised by diffuse or mixed Lauren type, HER2 IHC 2+, and low-level amplification. Kaplan-Meier survival analysis revealed that the heterogeneous overexpression was significantly associated with longer disease-free survival times than the homogeneous, and the high average GCN was most associated with poor outcome. Also, there was a strong correlation between the IHC and FISH results for each spot. Quantitative PCR analysis of the cancer tissues and the cell-free plasma showed that HER2 gene copy by quantitative PCR on tissue correlated well with those by FISH, but plasma HER2 level was not.Conclusions: Considering the high incidence of intratumoral HER2 heterogeneity in GC, accurate HER2 assessment would require larger tissues and more detailed guidelines. The guidelines should include the recommendation that FISH-scoring areas be selected with reference to a corresponding IHC slide. Also, the definition of HER2-positive tumours should be reassessed considering the intratumoral heterogeneity. Citation Format: Hye Seung Seung Lee, Hee Eun Lee, Kyoung Un Park, Soo Kyung Nam, Do Joong Park, Hyung-Ho Kim. Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2383. doi:10.1158/1538-7445.AM2013-2383
Abstract Background Although FOXO transcription factors may have an anti-angiogenic role, little is known about their role in tumor angiogenesis. The present study was performed to investigate the correlation between the constitutive expression of phosphorylated FOXO1 (pFOXO1) and angiogenesis in gastric cancer. Methods Immunohistochemistry was performed on tissue array slides containing 272 gastric carcinoma specimens, and the correlations between the cytoplasmic pFOXO1 expression in gastric cancer cells and CD34-immunopositive microvessel area (MVA) or the expressions of angiogenesis-related molecules were analyzed. In vitro analyses with Western blotting and semiquantitative reverse transcription-polymerase chain reaction were performed using the stable SNU-638 gastric cancer cell line transfected with lentivirus-delivered FOXO1 short hairpin RNA. Results The cytoplasmic expression of pFOXO1 in tumor cells was observed in 85% of gastric carcinoma cases, and was found to be positively associated with higher MVA ( P = 0.048). Moreover, pFOXO1 expression was positively correlated with the expressions of several angiogenesis-related proteins, including hypoxia inducible factor-1α (HIF-1α, P = 0.003), vessel endothelial growth factor ( P = 0.004), phosphorylated protein kinase B ( P < 0.001), and nuclear factor-κB ( P = 0.040). In contrast, the expression of pFOXO1 was not correlated with that of phosphorylated signal transducer and activator of transcription 3 or β-catenin. In addition, cell culture experiments showed that FOXO1 suppression increased the mRNA and protein expressions of HIF-1α. Conclusion Our results suggest that pFOXO1 expression in cancer cells plays a role in gastric cancer angiogenesis via mechanisms involving various angiogenesis-related molecules. Animal experiments are needed to confirm the anti-angiogenic role of FOXO1 in human gastric cancer.
Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment.Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity.This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1).This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications.Strong predictive markers are essential to improve response to immunotherapy.Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC.Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy.Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.
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