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Endometrial carcinomas arising in a bicornuate uterus are rare, only five case of which have been previously reported. We present a case of endometrial cancer arising in a bicornuate uterus, occurring in a 65-year-old woman. Unlike previously reported cases, our case showed mixed endometrial adenocarcinoma and undifferentiated carcinoma in one horn and focal adenocarcinoma in the other. Adequate tissue sampling of both horns is necessary for accurate diagnosis of malignancy in patients with a bicornuate uterus. Physicians should be aware of the possibility of this abnormality in cases when endometrial cancer is suspected but histology fails to confirm.

DNA methylation change is known to play a crucial role in early gastric carcinogenesis. The present study aimed to identify and validate the correlation between differentially methylated regions (DMRs) and the subtypes of early gastric cancers (EGCs). Illumina Infinium methylation assay (IIMA; 450K BeadChip kit) was performed on fresh tumor and non‑tumor tissues of 12 EGCs to screen the methylation status of 450,000 CpG sites. To evaluate the significance of DNA methylation in each histologic subtype, pyrosequencing assay (PA) was performed on 38 EGCs (18 intestinal-, 12 mixed- and 8 diffuse-type) using 12 genes selected from the screening. Between tumors of the intestinal-type (n=6), and diffuse- (n=4) plus mixed-types (n=2), 169 regions showed significant differences (intensity>3,000, Δβ>0.2) in IIMA. Hierarchical clustering using the 169 DMRs revealed distinct separation between the two groups. In PA using 12 selected genes from the IIMA results, the aberrant methylation statuses of DVL2 (p=0.0186) and ETS1 (p=0.0222) were significantly related to diffuse- and mixed-types rather than the intestinal-type, while C19orf35 (p=0.019) and CNRIP1 (p=0.0473) were related to the diffuse‑type rather than intestinal‑type, and GAL3ST2 (p=0.0158) and ITGA3 (p=0.0273) were related to the mixed-type rather than the other two types. The methylation of other genes, CLIP4, XKR6, CCDC57, MAML3 and SDC2, was related with age, tumor location, or Helicobacter infection rather than the histologic subtype. Aberrant DNA methylation of certain genes may be independently involved in each histologic subtype of EGC. Furthermore, mixed-type EGCs may be a distinctive histologic subtype based on the different subset of DMRs compared to those of other subtypes.

CD133, putative cancer stem cell marker, deemed to aid chemoresistance. However, this claim has been challenged recently and we previously reported that patients with CD133(+) colon cancer have benefit from 5-fluorouracil (5-FU) chemotherapy incontrast to no benefit in patients with CD133(-) cancer. To elucidate the role of CD133 expression in chemoresistance, we silenced the CD133 expression in a colon cancer cell line and determined its effect on the biological characteristics downstream. We comparatively analyzed the sequential changes of MDR1, ABCG2, AKT1 and survivin expression and the result of proliferation assay (WST-1 assay) with 5-FU treatment in CD133(+) and siRNA-induced CD133(-) cells, derived from Caco-2 colon cancer cell line. 5-FU treatment induced significantly increase of the mRNA expression of MDR1, ABCG2 and AKT1genes, but not protein level. CD133 had little to no effect on the mRNA and protein expression of these genes. However, survivin expression at mRNA and protein level were significantly increased in CD133(+) cells compared with siRNA-induced CD133-cells and Mock (not sorted CD133(+) cells) at 96 h after siRNA transfection. The cytotoxicity assay demonstrated notable increase of chemoresistance to 5-FU treatment (10 μM) in CD133(+) cells at 96 h after siRNA transfection. From this study, we conclude that CD133(+) cells may have chemoresistance to 5-FU through the mechanism which is related with survivin expression, instead of MDR1, ABCG2 and AKT1 expression. Therefore a survivin inhibitor can be a new target for effective treatment of CD133(+) colon cancer.

Antitumor immune response is suggested to be a factor affecting the number of nodes retrieved after colorectal cancer surgery. The purpose of this study was to evaluate the correlation of antitumor immune response with the number of retrieved nodes.Patients with colorectal cancer (n=63, TNM stage II and III) were enrolled. Inflammatory cell infiltration (ICI) was assessed on hematoxylin and eosin staining and T-cell markers (CD3, CD8, CD45RO) were evaluated using immunohistochemical methods.On univariate analysis, high ICI, CD3 and CD8 expression were associated with a greater number of nodes being retrieved. On multivariate analysis, tumors of the right colon (p=0.01) and high ICI (p=0.04) were independent predictors of a greater retrieval of nodes. TNM stage III tumor with low ICI was associated with reduced cancer-specific survival (p=0.02).ICI influences the number of nodes retrieved and affects survival of patients with stage III disease. Antitumor immune response may be an underlying factor determining the number of nodes retrieved after surgery for colorectal cancer.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are potentially malignant with variable biologic behavior that originates from neuroendocrine cells of digestive tract. Recently, the existence of cancer stem cells (CSC) was demonstrated in tumors of gastrointestinal tract. CD133 is a transmembrane glycoprotein that serves as a CSC marker in various malignancies. However, the expression of CD133 in neuroendocrine neoplasms (NEN) of digestive tract has not been studied. We evaluated tissue expression of CD133 by immunohistochemistry in 90 NENs of digestive tract with their matched non-neoplastic mucosa including stomach (n=15), small intestine (n=7), appendix (n=3), colon (n=8), rectum (n=41), pancreas (n=2), gallbladder (n=4) and liver (n=10). Tumors were divided according to 2010 WHO classification. CD133 was expressed in 30.3% (17/56) of well-differentiated neuroendocrine tumors (NET), 26.1% (6/23) of poorly-differentiated neuroendocrine carcinomas (NEC) and 63.6% (7/11) of mixed adenoneuroendocrine carcinoma (MANECs). MANEC refers to existence of both adenocarcinoma and NEC together, each one comprising at least 30% of the tumor. CD133 was expressed in cytoplasm, luminal-side of cell membrane, or both and the staining pattern correlated with tumor growth pattern. CD133 expression was not significantly correlated with tumor grade, site, expression of neuroendocrine markers (chromogranin-A and synaptophysin) and patients' survival. Thus, CD133 expression may lack prognostic significance in GEP-NETs. Importantly, CD133 was not detectable in non-neoplastic neuroendocrine cells of digestive system including pancreatic islets. In conclusion, CD133 is expressed in poorly-differentiated NECs and well-differentiated NETs of the digestive tract.

Background: The DNA methylation change is known to play a crucial role in early gastric carcinogenesis. However, its association with the histologic subtypes of EGCs has not been fully elucidated. In this study, we aim to know whether the subtypes of early gastric carcinomas (EGCs) are related to the differences of DNA methylation or not using genome wide methylation assay. Materials and Method: The comprehensive methylation analysis was performed by Illumina Infinium methylation assay (IIMA, 450K BeadChip kit) covering 450,000 sites on 12 tumors and 12 matched non-tumor mucosa from 12 patients with EGC. Hisytologically, the EGCs were devided into intestinal type (group A, n=6) and non-intestinal type (group B, diffuse=4 and mixed=2). The CpG sites in 450K microarray chip are classified into CpG islands, shores (2kb), shelves (2kb∼4kb) and open sea (>4kb) by CpG content and neighborhood context. According to the functional genomic distribution they are classified into promoter, body, 3′UTR and intergenic. To determine DMRs, average β-values were computed with β-values in signal intensity of over 3000. The Δβ-value was a result substracted average β-value of one from the other. When Δβ is over 0.2 or below -0.2, it was considered to be meaningful and refered to differentially methylated regions (DMRs) . Results: There were 484 DMRs in group A tumor and 208 DMRs in group B. The pattern of DMRs were different between two groups. In group A tumor, most of DMRs (97.73%) were hypermethylated and 75.26% were in CpG island. On the other hand, the group B tumors showed that 63.94% of DMRs were hypermethylated and only less than half of them (48.87%) were in CpG island. In terms of functional genomic distribution of DMRs, promoter (38.66%) was the most common site in group A while body (54.14%) was in group B. On Hierarchical clustering analysis, the clear grouping was made by 208 DMRs in three cases, two of them being mixed-type, by both correlation and Euclidean methods. However, no distinct grouping was found with DMRs in group A. Hierarchical clustering analysis of non-tumor mucosa showed a distinct separation between group A and B. Conclusions: DNA methylation pattern was distinctively different between the histologic subtype of EGCs. In the intestinal type of EGCs, the DNA methylation seems to be started in non-tumor mucosa. Citation Format: Khalilullah Mia-Jan, Hoon Ryu, Mi-Ra Lee, Sun-Young Ji, Mee-Yon Cho. Differences of DNA methylation patterns according to histologic subtypes of early gastric carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 421. doi:10.1158/1538-7445.AM2014-421

Background: The cancer stem cell (CSC) theory which postulates a small subset of tumor cells have the capacity in tumor initiation, progression and importantly resistance to chemotherapy. CD133 is a transmembrane glycoprotein that serves as a putative cancer stem cell (CSC) marker in colon cancer and its relationship with the chemoresistance has been on debate. In our previous clinical study, we found the patients with CD133+ colon cancer have better prognosis after 5 fluorouracil (5-FU) chemotherapy compared to CD133- tumors. Purpose: To understand the role of CSC marker expression in relation to chemoresistance in colon cancer, we evaluated the effect of CD133 inhibition in colorectal cancer (CRC) cell line on the genes expression which are related to chemoresistance or cell survival. Materials & Methods: CD133 siRNA transfection was performed on CD133+ colon cancer cell line (Caco-2). The proliferation assay used to detect the cytotoxic effect of 5-FU chemotherapy. The change in expression of chemoresistance related genes (AKT1, ABCG2 and MDR1) and cell survival related genes (survivin and beta-catenin) were evaluated by qRT-PCR and western blotting at 48hrs and 72hrs after CD133 siRNA transfection. Results: The proliferation assay demonstrated the increased chemoresistance of colon cancer cells after inhibition of CD133 expression when 5µM 5-FU was treated (p=0.0014). The mRNA expression of chemoresistance related genes (AKT1, ABCG2, MDR1) and cell survival related genes (survivin and β-catenin) were all significantly increased after transfection (p Citation Format: Mi-Ra Lee, Sun-Young Ji, Khalilullah Mia-Jan, Mee-Yon Cho. Inhibition of CD133 expression induce the chemoresistance to 5-fluorouracil in the colon cancer cell line. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 219. doi:10.1158/1538-7445.AM2014-219

Background Cancer stem cells (CSCs) are notorious for their capacity of tumor progression, metastasis or resistance to chemo-radiotherapy. However, the undisputed role of cancer stem marker, CD133, in colorectal cancers (CRCs) is not clear yet. Methods We assessed 271 surgically-resected stage II and III primary CRCs with (171) and without (100) adjuvant therapy after surgery. CD133 expression was analyzed by immunohistochemical (IHC) staining and real-time RT-PCR. CD133 promoter methylation was quantified by pyrosequencing. Results The CD133 IHC expression was significantly correlated with mRNA expression (p=0.0257) and inversely correlated with the promoter methylation (p=0.0001). CD133 was expressed more frequently in rectal cancer (p=0.0035), and in moderately differentiated tumors (p=0.0378). In survival analysis, CD133 expression was not significantly correlated with overall survival (OS) (p=0.9689) as well as disease-free survival (DFS) (p=0.2103). However, CD133+ tumors were significantly associated with better OS in patients with adjuvant therapy compared to those without adjuvant therapy (p Conclusions In stage II and III CRCs, CD133 IHC expression may signify the benefit for adjuvant therapy although it is not an independent prognostic factor.

Gastric cancer is one of the most common forms of malignancy and is associated with high mortality, ranked third for cancer death in Korea in 2009. Fatality has been reported in 23% of patients, which is probably due to patient presentation with advanced disease. In spite of a steady decline in both the incidence and mortality of gastric carcinoma, the incidence of diffuse carcinoma localized to the proximal stomach has been increasing. It has been suggested that epigenetic abnormalities might play a critical role in the earliest steps of cancer initiation. Recent studies suggested that the abnormal epigenetic silencing of genes occurs frequently during the early stages of the neoplastic process, such as the precancerous stage of tumor development. Specifically, gene silencing by aberrant methylation of CpG dinucleotide-rich areas, known as CpG islands (CGIs), has been suggested during oncogenesis. Moreover, frequent CGI methylation in early gastric carcinogenesis has been documented in the literature. Two major histological types of gastric adenocarcinoma, i.e., the intestinal and diffuse types, are based on the Lauren’s classification. Different pathogeneses and genetic alterations have been proposed for these two distinctive histological types. The more frequent intestinal type is often preceded by sequential steps of precancerous changes, whereas the diffuse type of gastric carcinoma tends to arise de novo, and is less commonly associated with dysplasia or adenoma. Similarly, two morphologically distinct gastric precancerous lesions of adenoma and flat dysplasia have been documented. In European countries and North America, adenomatous lesion usually refers to the neoplastic proliferation that produces a discrete, protruding lesion, whereas in Japan adenoma includes all types. On the basis of the similarities between the morphological and genetic aspects of colorectal and gastric cancers, it has been postulated that some gastric carcinoma may arise from either gastric adenomas or flat dysplasias, similar to the colorectal adenoma-carcinoma sequence. Given that the epigenetic regulation of carcinogenesis plays a role during a relatively early phase, different genetic and epigenetic alterations separating the two lesions are expected to exist. Findings from several studies indicated the necessity of considering the histologic type of gastric adenocarcinoma, because CpG Island Methylation According to the Histologic Patterns of Early Gastric Adenocarcinoma