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Abstract Background The clinicopathological features and endoscopic characteristics under magnifying endoscopy with narrow band imaging (ME-NBI) between early-stage gastric-type differentiated adenocarcinoma (GDA) and intestinal-type differentiated adenocarcinoma (IDA) remain controversial. Methods Early gastric adenocarcinomas that underwent endoscopic submucosal dissection (ESD) in Nanjing Drum Tower Hospital between August 2017 and August 2021 were included in the present study. GDA cases and IDA cases were selected based on morphology and immunohistochemistry staining of CD10, MUC2, MUC5AC, and MUC6. Clinicopathological data and endoscopic findings in ME-NBI were compared between GDAs and IDAs. Results The mucin phenotypes of 657 gastric cancers were gastric (n = 307), intestinal (n = 109), mixed (n = 181) and unclassified (n = 60). No significant difference was observed in terms of gender, age, tumor size, gross type, tumor location, background mucosa, lymphatic invasion, and vascular invasion between patients with GDA and IDA. GDA cases were associated with deeper invasion than IDA cases (p = 0.007). In ME-NBI, GDAs were more likely to exhibit an intralobular loop patten, whereas IDAs were more likely to exhibit a fine network pattern. In addition, the proportion of none-curative resection in GDAs was significantly higher than that in IDAs (p = 0.007). Conclusion The mucin phenotype of differentiated early gastric adenocarcinoma has clinical significance. GDA was associated with less endoscopically resectability than IDA.

In recent years, there have been significant advances in the endoscopic resection (ER) procedures of superficial nonampullary duodenal epithelial tumors (SNADETs). A preoperative endoscopic diagnosis is thus deemed necessary in determining the indication for subsequent ER. For the histologic and endoscopic diagnosis of SNADETs, understanding the mucin phenotype is inevitable. Recently, two diagnostic algorithms for the differential diagnosis of SNADETs from nonneoplastic lesions under magnifying endoscopy with narrow‐band imaging have been proposed. In addition, various endoscopic approaches have been proposed to differentiate low‐ and high‐grade adenomas/carcinomas, including white light endoscopy, magnifying image‐enhanced endoscopy, and endocytoscopy. These methods, however, have not been standardized with respect to the classification of their findings and the validation of their diagnostic accuracy. Moreover, there are still concerns with respect to the histologic criteria required to establish a SNADETs diagnosis. Standardization in the histologic and endoscopic diagnosis of SNADETs is needed. [ABSTRACT FROM AUTHOR]

Background: The clinicopathological features and endoscopic characteristics under magnifying endoscopy with narrow band imaging (ME-NBI) between early-stage gastric-type differentiated adenocarcinoma (GDA) and intestinal-type differentiated adenocarcinoma (IDA) remain controversial. Methods: Early gastric adenocarcinomas that underwent endoscopic submucosal dissection (ESD) in Nanjing Drum Tower Hospital between August 2017 and August 2021 were included in the present study. GDA cases and IDA cases were selected based on morphology and immunohistochemistry staining of CD10, MUC2, MUC5AC, and MUC6. Clinicopathological data and endoscopic findings in ME-NBI were compared between GDAs and IDAs. Results: The mucin phenotypes of 657 gastric cancers were gastric (n = 307), intestinal (n = 109), mixed (n = 181) and unclassified (n = 60). No significant difference was observed in terms of gender, age, tumor size, gross type, tumor location, background mucosa, lymphatic invasion, and vascular invasion between patients with GDA and IDA. GDA cases were associated with deeper invasion than IDA cases (p = 0.007). In ME-NBI, GDAs were more likely to exhibit an intralobular loop patten, whereas IDAs were more likely to exhibit a fine network pattern. In addition, the proportion of none-curative resection in GDAs was significantly higher than that in IDAs (p = 0.007). Conclusion: The mucin phenotype of differentiated early gastric adenocarcinoma has clinical significance. GDA was associated with less endoscopically resectability than IDA. [ABSTRACT FROM AUTHOR]

Abstract Background Small bowel adenocarcinomas (SBAs) are rare and there is little comprehensive data on SBA genomic alterations for Asian patients. This study aimed to profile genomic alterations of SBA in Japanese patients using targeted next-generation sequencing (NGS). Methods We examined 22 surgical resections from patients with primary SBA. SBA genomic alterations were analyzed by NGS. Mismatch repair (MMR) status was determined by immunohistochemical analysis. Mucin phenotypes were classified as gastric (G), intestinal (I), gastrointestinal (GI), and null (N) types on MUC2, MUC5AC, MUC6, and CD10 immunostaining. Results The most common genomic alterations found in SBA tumors were TP53 (n = 16), followed by KRAS (n = 6), APC (n = 5), PIK3CA (n = 4), CTNNB1 (n = 3), KIT (n = 2), BRAF (n = 2), CDKN2A (n = 2), and PTEN (n = 2). Deficient MMR tumors were observed in 6 out of 22 patients. Tumor mucin phenotypes included 2 in G-type, 12 in I-type, 3 in GI-type, and 5 in N-type. APC and CTNNB1 mutations were not found in G-type and GI-type tumors. KRAS mutations were found in all tumor types except for G-type tumors. TP53 mutations were found in all tumor types. Although no single gene mutation was associated with overall survival (OS), we found that KRAS mutations were associated with significant worse OS in patients with proficient MMR tumors. Conclusions SBA genomic alterations in Japanese patients do not differ significantly from those reports in Western countries. Tumor localization, mucin phenotype, and MMR status all appear to impact SBA gene mutations.

Introduction: This study aimed to identify the characteristics of superficial non-ampullary duodenal epithelial tumors (SNADETs) based on the mucin phenotype using magnifying narrow-band imaging with acetic acid spray (MA-NBI) and evaluate the efficacy of MA-NBI in differentiating gastric-type (G-type) from intestinal-type (I-type) lesions. Methods: We retrospectively identified 59 resected SNADETs in 59 patients who underwent MA-NBI. We evaluated surface patterns using MA-NBI to differentiate G-type from I-type lesions. Surface structures were classified into three patterns: tubular, villous, or oval structures. Lesions displaying a single pattern among the three patterns were classified as monotype, whereas those displaying multiple surface patterns were classified as mixed type. In addition, lesions with disorganized and unclear structures with irregular margins were classified as irregular surface structures. Results: In total, 32 (54%), 26 (44%), and 1 (2%) lesions were classified as Vienna category 3, 4, and 5 tumors, respectively, whereas 49 (83%) and 10 (17%) were classified as I- and G-type lesions, respectively. Oval structures were more frequently observed in G-type lesions (70%), whereas tubular structures were more frequently observed in I-type lesions (78%) (p < 0.001). Category 4 and 5 lesions had significantly higher mixed and irregular surface structure rates than category 3 lesions (41 vs. 6%, p = 0.003 and 81 vs. 3%, p < 0.001, respectively). Conclusion: MA-NBI can distinguish the mucin phenotypes of SNADETs and may facilitate histological grade diagnosis. [ABSTRACT FROM AUTHOR]

Background: Small bowel adenocarcinomas (SBAs) are rare and there is little comprehensive data on SBA genomic alterations for Asian patients. This study aimed to profile genomic alterations of SBA in Japanese patients using targeted next-generation sequencing (NGS).Methods: We examined 22 surgical resections from patients with primary SBA. SBA genomic alterations were analyzed by NGS. Mismatch repair (MMR) status was determined by immunohistochemical analysis. Mucin phenotypes were classified as gastric (G), intestinal (I), gastrointestinal (GI), and null (N) types on MUC2, MUC5AC, MUC6, and CD10 immunostaining.Results: The most common genomic alterations found in SBA tumors were TP53 (n = 16), followed by KRAS (n = 6), APC (n = 5), PIK3CA (n = 4), CTNNB1 (n = 3), KIT (n = 2), BRAF (n = 2), CDKN2A (n = 2), and PTEN (n = 2). Deficient MMR tumors were observed in 6 out of 22 patients. Tumor mucin phenotypes included 2 in G-type, 12 in I-type, 3 in GI-type, and 5 in N-type. APC and CTNNB1 mutations were not found in G-type and GI-type tumors. KRAS mutations were found in all tumor types except for G-type tumors. TP53 mutations were found in all tumor types. Although no single gene mutation was associated with overall survival (OS), we found that KRAS mutations were associated with significant worse OS in patients with proficient MMR tumors.Conclusions: SBA genomic alterations in Japanese patients do not differ significantly from those reports in Western countries. Tumor localization, mucin phenotype, and MMR status all appear to impact SBA gene mutations. [ABSTRACT FROM AUTHOR]

Our previous study of duodenal adenoma using an endocytoscopy system (ECS) demonstrated that disappearance of goblet cells and spindle-shaped nuclei with loss of polarity were characteristic features. In addition, round duct openings and finger-like projections were observed in tubular adenoma and villous adenoma, respectively. Here, we retrospectively investigated six cases of histologically proven sporadic non-ampullary mucosal duodenal cancer (NAMDC) using ECS. Immunohistochemistry for CD10, MUC2, MUC5AC, and MUC6 was employed to determine the mucin phenotype in addition to conventional HE histology. Immunohistochemistry revealed one case involving the duodenal bulb that was considered to be the mixed type. The other five cases, located in the second or third portion, were considered to be the intestinal type. Vital staining of the mixed-type case was considered insufficient for ECS observation because of surface mucus. However, all five cases of intestinal-type duodenal cancer demonstrated a villous structure, disappearance of goblet cells and enlarged nuclei with loss of polarity. Tubular structures were admixed in four of those cases. Four cases demonstrated oval-shaped nuclei, and one case had spindle-shaped nuclei. Cases showing spindle-shaped nuclei in most of the lesion were diagnosed histologically as cancer in adenoma where the adenomatous component of the tumor was dominant. Oval-shaped nuclei and nuclear enlargement are the characteristic features of NAMDC revealed by ECS and are included among the histological criteria used for diagnosis. ECS offers the potential to perform real-time histological diagnosis of NAMDC in vivo.

Objectives: Mucin phenotype is a tool to classify gastric cancer, but the relationship between mucin phenotype and its malignancy is still controversial. This study aimed to clarify the relationship between mucin phenotype and the malignant potential of gastric cancer. Methods: A total of 82 cases of early-stage differentiated adenocarcinoma (submucosal invasion cases) obtained from surgeries were studied by immunohistochemistry. Gastric mucin phenotype and E-cadherin expression were analyzed in the mucosal and submucosal layer. E-cadherin expression was analyzed by using imaging software (ImageJ) for objective data analysis. Furthermore, the mucin phenotypic shift was analyzed from mucosa to submucosa. Results: We found that: (1) tumors with intestinal mucin phenotype had statistically more venous invasion in the submucosal lesion; (2) tumors with an intestinal phenotype that showed venous invasion in the submucosal lesion had a higher percentage of tumors that showed loss of phenotype; (3) no dominant change in E-cadherin expression was observed from the mucosa to submucosa. Conclusion: Tumors with loss of phenotype and submucosal intestinal phenotype showed predominantly more venous invasion, so examining the identification of phenotypes and phenotype shifts can be expected to be a factor that influences treatment strategies after endoscopic treatment or after surgical resection. [ABSTRACT FROM AUTHOR]

Aims: We aimed to clarify the endoscopic/clinicopathological features of superficial non-ampullary duodenal epithelial tumors (SNADETs) based on their mucin phenotypes. Methods: We analyzed 62 SNADET lesions and classified them based on mucin phenotypic expression. Endoscopic and clinicopathological findings were compared according to mucin phenotypes. Results: Eleven lesions had the gastric phenotype (GP) and 43 lesions had the intestinal phenotype (IP). All GP lesions were located in the first portion of the duodenum, while most IP lesions (72.1%) were located in the second portion (p < 0.01). Tumor size was significantly larger in the GP than in the IP group (14.4 mm vs. 10.2 mm, p < 0.05). Reddish color (72.7% in GP vs. 37.2% in IP, p < 0.05), type 0-I (72.7% vs. 11.6%, p < 0.01), lobular/granular pattern (81.8% vs. 4.7%, p < 0.01), and category 4/5 in Vienna classification (81.8% vs. 30.2%, p < 0.01) were observed significantly more often in the GP than in the IP group. Regarding findings of magnifying endoscopy with narrow-band imaging (M-NBI), white opaque substance (22.2% in GP vs. 89.7% in IP, p < 0.01) and light blue crest (0% vs. 43.6%, p < 0.05) were significantly less frequently observed in the GP group. Oval-shaped marginal epithelium (66.7% vs. 17.9%, p < 0.01), dense pattern (55.6% vs. 2.6%, p < 0.01), and dilatation of the intervening part (100% vs. 12.8%, p < 0.01) were more frequently observed in the GP group. Conclusions: SNADETs showed distinct endoscopic/clinicopathological features according to the mucin phenotype. Tumor location, coloration, macroscopic type, and endoscopic findings including M-NBI are useful to distinguish the mucin phenotypes of SNADETs. [ABSTRACT FROM AUTHOR]

Background/Aims: To evaluate gastric early differentiate-type carcinogenesis, we attempted to identify clinicopathological and biological differences in differentiated-type minute intramucosal neoplasia (MIMN), which was defined as a tumor with a diameter of < 5 mm. Methods: We examined clinicopathological findings and biological factors, including TP53 overexpression, mucin phenotype, Ki-67-positive rate, MLH1, intranuclear accumulation of β-catenin, and DNA methylation status (low methylation epigenotype [LME], intermediate methylation epigenotype, and high methylation epigenotype [HME]) in MIMNs. In addition, non-MIMNs were also analyzed. In the present study, MIMN and non-MIMN were also examined based on low-grade dysplasia, high-grade dysplasia, and intramucosal cancer (IMC). Results: In clinicopathological findings, there were significant differences in sex ratios and tumor locations between MIMNs and non-MIMNs. Among the examined biological factors, no significant differences in the frequencies of biological factors were observed between the 2 intramucosal neoplasia types. However, the frequency of intranuclear accumulation of β-catenin was higher in non-MIMNs than in MIMNs. Finally, although the frequency of HME was significantly lower in MIMNs than in non-MIMNs, the opposite was observed for LME. Conclusions: The current finding suggested that DNA methylation and accumulation of β-catenin were closely associated with tumor development from MIMN to non-MIMN. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a heterogeneous disease that develops through stepwise accumulation of genetic alterations and progresses via several distinct pathways. However, the tumorigenesis of CRCs with BRAF non-V600E mutations remains unclear. Here, we aimed to elucidate the tumorigenesis of CRCs with BRAF non-V600E mutations, focusing on differences in mucin phenotype and genetic alterations between CRCs with non-V600E and V600E mutations. We investigated 201 patients with CRC and performed panel testing of 415 genes to identify BRAF mutations. Patients were classified into five mucin phenotypes - large-intestinal, small-intestinal, gastric, mixed, and unclassified - using immunohistochemistry for CD10, MUC2, MUC5AC, and MUC6. BRAF mutations were identified in 24 of 201 patients' samples, of which 13 (6.5%) had a V600E mutation (V600E-mutant) and 11 (5.5%) had non-V600E mutations (non-V600E-mutant). MUC5AC expression was significantly associated with V600E mutations (P = 0.040), while CD10 expression was significantly associated with non-V600E mutations (P = 0.010). The small-intestinal mucin phenotype was significantly associated with non-V600E mutations (P = 0.031), while the mixed mucin phenotype was significantly associated with V600E mutations (P = 0.027). Regarding genetic alterations, focusing on the WNT signaling pathway, APC mutation was significantly associated with non-V600E mutations (P < 0.001), while RNF43 mutation was significantly associated with V600E mutations (P = 0.020). Considering the differences in mucin phenotype and genetic alterations, different modes of tumorigenesis are assumed for CRC with BRAF V600E mutation and non-V600E mutations. These findings are important in understanding the biology and treatment strategies for BRAF-mutant CRC., Competing Interests: Declaration of competing interest All authors have no conflicts of interest regarding this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Our previous study of duodenal adenoma using an endocytoscopy system (ECS) demonstrated that disappearance of goblet cells and spindle-shaped nuclei with loss of polarity were characteristic features. In addition, round duct openings and finger-like projections were observed in tubular adenoma and villous adenoma, respectively. Here, we retrospectively investigated six cases of histologically proven sporadic non-ampullary mucosal duodenal cancer (NAMDC) using ECS. Immunohistochemistry for CD10, MUC2, MUC5AC, and MUC6 was employed to determine the mucin phenotype in addition to conventional HE histology. Immunohistochemistry revealed one case involving the duodenal bulb that was considered to be the mixed type. The other five cases, located in the second or third portion, were considered to be the intestinal type. Vital staining of the mixed-type case was considered insufficient for ECS observation because of surface mucus. However, all five cases of intestinal-type duodenal cancer demonstrated a villous structure, disappearance of goblet cells and enlarged nuclei with loss of polarity. Tubular structures were admixed in four of those cases. Four cases demonstrated oval-shaped nuclei, and one case had spindle-shaped nuclei. Cases showing spindle-shaped nuclei in most of the lesion were diagnosed histologically as cancer in adenoma where the adenomatous component of the tumor was dominant. Oval-shaped nuclei and nuclear enlargement are the characteristic features of NAMDC revealed by ECS and are included among the histological criteria used for diagnosis. ECS offers the potential to perform real-time histological diagnosis of NAMDC in vivo. [ABSTRACT FROM AUTHOR]

Background and Aims: We aimed to investigate an association between clinicopathological features, including immunohistochemical mucin phenotypes, and magnifying chromoendoscopic findings with crystal violet staining (ME-CV) in non-ampullary duodenal epithelial tumors (NADETs). Methods: A total of 55 patients with NADET were divided into 3 groups by mucin phenotype: intestinal, gastrointestinal, or gastric. ME-CV findings were classified into 4 patterns: convoluted, leaf-like, reticular/sulciolar, and pinecone. The clinicopathological features and ME-CV findings were compared among the mucin phenotypes. Results: Tumors of the gastric type were located in the duodenal bulb (p < 0.001), and contained pyloric gland adenoma (p < 0.001) more frequently than the other types. White-light endoscopy indicated that milk-white mucosa was less frequent in tumors of the gastric type than in those of the gastrointestinal type (p = 0.006) and the intestinal type (p < 0.001). ME-CV findings were significantly different between the gastric type and the other type (p = 0.028). Totally, 5 of 8 tumors of the gastric type manifested a pinecone pattern, 4 of which were compatible with pyloric gland adenoma. Conclusions: The endoscopic findings of NADETs differ according to mucin phenotype. A pinecone pattern under ME-CV may be characteristic of NADETs of the gastric type, especially pyloric gland adenoma. [ABSTRACT FROM AUTHOR]

Aims Extra-ampullary duodenal adenoma ( EADA) is a rare condition with poorly described clinicopathological details. In this study, we aimed to characterize EADA clinicopathologically. Methods and results We performed a retrospective review of 44 serial cases of EADA. Each EADA was categorized as either gastric-type ( n = 5) or intestinal-type ( n = 39). All gastric-type adenomas were located in the first portion of the duodenum and exhibited a pedunculated shape. Gastric-type adenomas were classified into two subtypes: pyloric gland and foveolar. The former consisted of mucin 6 ( MUC6)-positive glands covered with MUC5 AC-positive cells, whereas nearly all the latter consisted of MUC5 AC-positive cells. When EADAs were categorized into high and low grades, approximately 40% (16 of 44) were high-grade. The high-grade adenomas were significantly larger than the low-grade adenomas (19.4 ± 8.6 mm versus 11.8 ± 5.1 mm, P = 0.021), and all adenomas greater than 20 mm in largest diameter were categorized as high-grade adenomas. Among 16 individuals who underwent total colonoscopy before or after duodenal mucosal resection, nine had a colorectal neoplasm, and all nine duodenal lesions were of the intestinal phenotype. Conclusions We clarified the clinicopathological characteristics of gastric- and intestinal-type EADAs. EADAs greater than 20 mm at the largest diameter were consistently high-grade, and are thought to have the potential to progress to adenocarcinoma. These findings should be helpful for the clinical management of EADA. [ABSTRACT FROM AUTHOR]

A total of 313 cases of differentiated-type early gastric adenocarcinomas, including 113 cases of small-sized carcinoma (5< × ≤10 mm) and 121 cases of microcarcinoma (0< × ≤5 mm), were examined immunohistochemically to clarify the phenotypic expressions. They were classified into four categories (gastric phenotype (G-type), intestinal phenotype, gastrointestinal phenotype, and null phenotype) by a two-step process: the phenotype based on an immunoprofile of mucin core proteins (MUCs) with CDX2 (w/.CDX2-assessment); and the phenotype of MUCs only (w/o.CDX2-assessment). CDX2 expression was observed in 89.1% (279/313); it was highly expressed in 87.6% (106/121) of microcarcinomas. MUC2 expression increased as tumor size increased ( P < 0.05). Compared with w/o.CDX2-assessment, w/.CDX2-assessment showed significantly fewer G-type carcinomas ( P < 0.05). Each phenotype marker was less expressed in the submucosal part than in the mucosal part. In conclusion, CDX2 was a sensitive marker for assessing intestinal phenotype. A large portion of the early differentiated-type adenocarcinomas expressed CDX2 from the very early stage of carcinogenesis, and the proportion of G-type was unexpectedly low. Lower expression of each phenotype marker was considered the cause of phenotype alteration during submucosal invasion. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is the fifth commonest malignancy worldwide and still one of the leading causes of cancer-related death. The aim of this study was to identify a novel prognostic marker or therapeutic target for GC. Methods: We analyzed candidate genes from our previous Escherichia coli ampicillin secretion trap (CAST) libraries in detail, and focused on the FKTN gene because it was overexpressed in both GC cell line CAST libraries, MKN-1 and MKN-45. Results: Quantitative reverse transcriptase PCR analysis of FKTN revealed that FKTN messenger RNA was overexpressed in nine of 28 (32.1 %) GC tissue samples compared with nonneoplastic gastric mucosa. Immunostaining of fukutin showed that 297 of 695 cases (42.7 %) were positive for fukutin. Fukutin-positive GC cases were significantly associated with differentiated histological features, and advanced T grade and N grade. In addition, fukutin expression was observed more frequently in the intestinal phenotype (51 %) of GC than in other phenotypes (37 %) when defined by the expression patterns of mucin 5AC, mucin 6, mucin 2, and CD10. FKTN small interfering RNA treatment decreased GC cell proliferation. Conclusions: These results indicate that the expression of fukutin may be a key regulator for progression of GC with the intestinal mucin phenotype. [ABSTRACT FROM AUTHOR]

Adipophilin, a lipid droplet-associated protein that regulates lipid droplet structure and formation, is expressed in a wide variety of tumors. The aims of this study were to evaluate the frequency and distribution pattern of adipophilin expression in gastric epithelial neoplasia and to correlate these variables with clinicopathological features and the mucin phenotype. We retrospectively examined 159 cases of gastric epithelial neoplasia, which were classified according to the Vienna classification system as 52 noninvasive low-grade adenoma (category 3), 65 noninvasive high-grade neoplasia (category 4), and 42 invasive neoplasia (category 5). Immunohistochemistry for adipophilin was performed, and phenotypic marker expression was determined by immunohistostaining with MUC2, MUC5AC, CD10, MUC6, and villin. Adipophilin was expressed in 41 of the 52 (79 %) category 3 cases, in 42 of the 65 (65 %) category 4 cases, and in 23 of the 42 (55 %) category 5 cases. Expression of adipophilin was only present in lesions with complete or incomplete intestinal phenotypes. Adipophilin was expressed more frequently in the surface epithelium in category 3, whereas there was a stepwise increase in cryptal staining of adipophilin from category 3 to category 5. In conclusion, adipophilin expression is closely related to the intestinal differentiation of the tumor. The pattern of immunostaining for adipophilin might be a useful new marker for discriminating adenomas from adenocarcinomas. [ABSTRACT FROM AUTHOR]

Background: Early detection and treatment of non-invasive neoplasms can effectively reduce the incidence of advanced gastric carcinoma (GC), but only when the lineage is continuous between non-invasive and advanced tumours. Although a fraction of non-invasive neoplasms progress to invasive GC, it is difficult to identify individual progression-prone non-invasive neoplasms. To classify non-invasive gland-forming gastric neoplasms into clusters of different levels of progression risk, we applied mucin phenotyping and genomic DNA microarray analyses to intramucosal gland-forming gastric neoplasms. Methods: Formalin-fixed, paraffin-embedded tissues from 19 non-invasive and 24 invasive gland-forming neoplasms were obtained via endoscopic submucosal dissection or surgical excision. According to the Vienna classification, intramucosal neoplasms were classified as low-grade or high-grade non-invasive neoplasms (LGNs [category 3] and HGNs [category 4], respectively) or invasive carcinomas (intramucosal GCs and mucosal parts of submucosal or deeper GCs [category 5]). Neoplastic lesions were characterized by mucin phenotypes determined using monoclonal antibodies against MUC2, MUC5AC, MUC6, and CD10. Genomic DNA samples from mucosal neoplasms were subjected to array-based comparative genomic hybridization and subsequent unsupervised, hierarchical clustering with selected large-sized genes. Results: There was no significant difference in mucin phenotype between HGNs/LGNs and invasive carcinomas. The clustering classified samples into stable, unstable, and intermediate. The histological tumour grade or mucin phenotype of non-invasive neoplasms did not correlate with the clustering results. Each cluster may represent an independent lineage of different outcome because the size distribution of non-invasive tumours among the 3 clusters almost overlapped. In contrast, the unstable cluster alone included invasive carcinomas. Conclusions: These findings suggest that the outcome of individual tumours is not stochastically determined but can be predicted from the genomic copy-number profile even at the non-invasive stage. Non-invasive neoplasms of the unstable clusters, which accounted for 21% of non-invasive neoplasms, may progress to invasive carcinomas, whereas those of stable cluster may not. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the third most common cause of cancer‑related death in the world. Annexin A10 (ANXA10), a member of the Annexin family, is a calcium‑/phospholipid‑binding protein; however, little is known concerning its functions. It is still unclear what molecule is involved in the induction of ANXA10. In the present study, we performed immunohistochemistry to evaluate the expression of ANXA10, pancreatic and duodenal homeobox‑1 (PDX1) and mucin phenotype markers in 130 GC samples. ANXA10 was detected in 63 (48%) of the 130 GC cases and loss of ANXA10 was significantly correlated with disease progression and poor clinical outcomes in GC. PDX1 was significantly correlated with ANXA10 in GC cases and cell lines. Although PDX1 was not significantly correlated with the GC cases with any of the mucin phenotypes, ANXA10 was preferentially detected in the GC cases with the gastric mucin phenotype. As a further investigation, we generated organoids derived from human GC and identified the duplication of the mucin phenotypes of GC by immunohistochemistry. The repression effect on cell growth that was observed in the ANXA10‑knockdown cell lines was also clearly observed in the human gastric organoids. We demonstrated that the expression of ANXA10 was correlated with the gastric mucin phenotype and ANXA10 was involved in the induction of PDX1 expression in GC. We also provided evidence that GC organoids represent a powerful tool for scrutinizing the biology of GC, especially with regard to the mucin phenotype.

Objective: Spheroid colony formation is a useful method of cancer stem cell (CSC) characterization. We previously showed that the IQ motif containing the GTPase-activating protein 3 gene (IQGAP3) is upregulated in spheroid body-forming gastric cancer (GC) cells compared with parental cells. We investigated IQGAP3 expression in GC., Methods: IQGAP3 protein expression was analyzed by immunohistochemistry in 165 GC cases. RNA interference was used to inhibit IQGAP3 expression in GC cell lines., Results: In non neoplastic gastric mucosa, weak staining of IQGAP3 was observed in the foveolar epithelium, while GC tissue showed stronger, more extensive staining. Of the 165 GC cases, 34 (21%) were positive for IQGAP3 expression. GC cases positive for IQGAP3 were found more frequently in stage II/III/IV cases than in stage I cases. Univariate and multivariate analyses demonstrated that IQGAP3 expression is an independent prognostic classifier of GC patients. Both the number and size of the spheres formed by MKN-74 cells were significantly reduced by knockdown of IQGAP3. The phosphorylation of Akt and Erk1/2 was inhibited by knockdown of IQGAP3., Conclusion: These results suggest that IQGAP3 plays an important role in gastric CSCs. The location of IQGAP3 on the cell membrane makes it a potential therapeutic target for GC., (© 2017 S. Karger AG, Basel.)