Gene Summary

Gene:MUC6; mucin 6, oligomeric mucus/gel-forming
Aliases: MUC-6
Summary:This gene encodes a member of the mucin protein family. Mucins are high molecular weight glycoproteins produced by many epithelial tissues. The protein encoded by this gene is secreted and forms an insoluble mucous barrier that protects the gut lumen. [provided by RefSeq, Dec 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Gastric Mucosa
  • Stomach Cancer
  • Stomach
  • Tandem Repeat Sequences
  • Adenocarcinoma
  • Colorectal Cancer
  • Cancer Gene Expression Regulation
  • Neoplasm Invasiveness
  • Mucin-2
  • Protein Binding
  • Risk Assessment
  • Pancreatic Cancer
  • Mucin-6
  • Sex Factors
  • RT-PCR
  • Phenotype
  • Young Adult
  • Immunohistochemistry
  • Mucin 5AC
  • Precancerous Conditions
  • p53 Protein
  • Cell Differentiation
  • Messenger RNA
  • Survival Rate
  • ras Proteins
  • Neoplasm Proteins
  • Mucins
  • DNA Mutational Analysis
  • Adenoma
  • Proto-Oncogene Proteins p21(ras)
  • Disease Progression
  • Statistics, Nonparametric
  • Mucinous Adenocarcinoma
  • Mutation
  • Transcription
  • Biomarkers, Tumor
  • Uterine Diseases
  • Chromosome 11
  • Gene Expression
  • Prostate Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MUC6 (cancer-related)

Kasprzak A, Adamek A
Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
Mucins are large

Lee HK, Kwon MJ, Seo J, et al.
Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in ALK-positive lung cancer: Comparison with EGFR-mutated lung cancer.
Pathol Res Pract. 2019; 215(3):459-465 [PubMed] Related Publications
ALK-positive (ALK+) lung adenocarcinoma usually shows a more advanced-staged disease with frequent nodal metastasis and highly aggressive outcomes compared with EGFR-mutated lung cancers. The aim of this study was to investigate the expression profiles of several mucins in ALK + lung cancers to gain insight into the relationship between the more aggressive biological nature of ALK + lung cancers and the role of mucins. We examined the immunohistochemical profiles of mucins MUC1, MUC2, MUC5AC, and MUC6 in 19 ALK + lung cancers compared with 42 EGFR-mutated lung cancers. ALK + cancers were found to occur in younger patients and were characterized by a solid-predominant histologic subtype with frequent signet ring cells and peritumoral muciphages. By contrast, EGFR-mutated cancers lacked ALK-specific histological patterns. Although all MUC1 and MUC5AC were expressed in both subtypes, MUC1 expression in ALK + cancers was visualized exclusively through cytoplasmic staining, whereas those in EGFR-mutated cancers were predominantly membranous staining in apical area (92.9%) and focally in cytoplasmic staining (7.1%). MUC5AC expression in ALK + cancers was exclusively visualized through cytoplasmic staining (100%), whereas EGFR-mutated cancers showed predominantly perinuclear dot-like patterns (90.5%) and focal cytoplasmic staining (9.5%). MUC2 and MUC6 expression was not detected in either type of lung cancer. CONCLUSIONS: The high frequency of both MUC1 and MUC5AC cytoplasmic expression, coupled with a lack of MUC2 and MUC6 expression in ALK + lung cancer may contribute to the biologically aggressive behavior of ALK + cancer. Inhibitors to these types of mucins may thus act as a barrier to cancerous extension reducing their aggressive behavior.

Murakami T, Akazawa Y, Yatagai N, et al.
Molecular characterization of sessile serrated adenoma/polyps with dysplasia/carcinoma based on immunohistochemistry, next-generation sequencing, and microsatellite instability testing: a case series study.
Diagn Pathol. 2018; 13(1):88 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway.
METHODS: We performed immunostaining for β-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma.
RESULTS: Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation.
CONCLUSIONS: SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/β-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.

Wiktorowicz M, Mlynarski D, Pach R, et al.
Rationale and feasibility of mucin expression profiling by qRT-PCR as diagnostic biomarkers in cytology specimens of pancreatic cancer.
Pancreatology. 2018; 18(8):977-982 [PubMed] Related Publications
BACKGROUND: Aberrantly expressed mucin glycoproteins (MUC) play important roles in pancreatic ductal adenocarcinoma (PDAC), yet their use as a diagnostic aid in fine-needle aspiration biopsy (FNAB) is poorly documented. The aim of this study was to investigate the rationale and feasibility of mucin (MUC1, MUC2, MUC3, MUC4, MUC5AC, and MUC6) expression profiling by RT-PCR for diagnostic applications in cytology.
METHODS: Mucin expression was examined by RT-PCR and immunohistochemistry in specimens resected from patients with pancreatic (n = 101), ampullary (n = 23), and common bile duct (n = 10) cancers and 33 with chronic pancreatitis. Furthermore, mucin profiling by RT-PCR was prospectively compared in surgical and biopsy specimens of 40 patients with pancreatic solid tumours qualified for FNAB prior to surgery.
RESULTS: A logistic regression model to distinguish PDAC from chronic pancreatitis using RT-PCR profiling included MUC3, MUC5AC, and MUC6. The same set of mucins differentiated ampullary and bile duct cancers from chronic pancreatitis. AUCs for the ROC curves derived from the two models were 0.95 (95%CI 0.87-0.99) and 0.92 (95%CI 0.81-0.98), respectively. The corresponding positive likelihood ratios were 6.02 and 5.97, while the negative likelihood ratios were 0.10 and 0.12. AUCs of ROC curves obtained by RT-PCR and immunohistochemistry demonstrated that both analytical methods were comparable. Surgical and cytological samples showed significantly correlated values of ΔCt for individual mucins with the overall Pearson's correlation coefficient r = 0.841 (P = 0.001).
CONCLUSIONS: Mucin expression profiling of pancreatic cancer with RT-PCR is feasible and may be a valuable help in discriminating malignant lesions from chronic pancreatitis in FNAB cytology.

Nakamura A, Yamaguchi K, Minamiguchi S, et al.
Mucinous adenocarcinoma, gastric type of the uterine cervix: clinical features and HER2 amplification.
Med Mol Morphol. 2019; 52(1):52-59 [PubMed] Related Publications
Mucinous adenocarcinoma, gastric type (GAS) is difficult to diagnose and shows poor prognosis. Trastuzumab, an anti-human epidermal growth factor type 2 (HER2) monoclonal antibody, is effective in HER2-positive stomach cancer. The objectives of this study were to identify the clinicopathological characteristics of GAS and to evaluate HER2 expression in GAS. We retrospectively reviewed 322 cervical cancer cases diagnosed at the Kyoto University Hospital from 2010 to 2016. The incidence, clinical factors including age, stage, and lymph node status, tumor markers, immunoreactive expression of MUC6, HIK1083, and HER2, and HER2 amplification were evaluated. Of the 322 cases of cervical cancer, 13 cases of the adenocarcinoma cases were diagnosed as GAS. Watery discharge, lower abdominal pain, CA19-9 elevation, and lymph node metastasis were frequently observed in GAS (p = 0.0226, p = 0.0400, p = 0.0346, and p = 0.0274, respectively). Immunohistochemistry showed positive MUC6 status in all 13 cases and positive HIK1083 status in 8 cases. The HER2 expression status was equivocal in six cases by immunohistochemistry and HER2 amplification was identified in one case. GAS exhibits frequent lymph node metastasis and clinical symptoms such as watery discharge and lower abdominal pain, high levels of CA19-9. In addition, some parts of GAS exhibit HER2 amplification.

Zhang X, Shi D, Liu YP, et al.
Effects of the Helicobacter pylori Virulence Factor CagA and Ammonium Ion on Mucins in AGS Cells.
Yonsei Med J. 2018; 59(5):633-642 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To investigate the effects of Helicobacter pylori (H. pylori)-CagA and the urease metabolite NH₄⁺ on mucin expression in AGS cells.
MATERIALS AND METHODS: AGS cells were transfected with CagA and/or treated with different concentrations of NH₄CL. Mucin gene and protein expression was assessed by qPCR and immunofluorescence assays, respectively.
RESULTS: CagA significantly upregulated MUC5AC, MUC2, and MUC5B expression in AGS cells, but did not affect E-cadherin and MUC6 expression. MUC5AC, MUC6, and MUC2 expression in AGS cells increased with increasing NH₄⁺ concentrations until reaching a peak level at 15 mM. MUC5B mRNA expression in AGS cells (NH₄⁺ concentration of 15 mM) was significantly higher than that at 0, 5, and 10 mM NH₄⁺. No changes in E-cadherin expression in AGS cells treated with NH₄⁺ were noted, except at 20 mM. The expression of MUC5AC, MUC2, and MUC6 mRNA in CagA-transfected AGS cells at an NH₄⁺ concentration of 15 mM was significantly higher than that at 0 mM, and decreased at higher concentrations. The expression of MUC5B mRNA increased with increases in NH₄⁺ concentration, and was significantly higher compared to that in untreated cells. No significant change in the expression of E-cadherin mRNA in CagA-transfected AGS cells was observed. Immunofluorescence assays confirmed the observed changes.
CONCLUSION: H. pylori may affect the expression of MUC5AC, MUC2, MUC5B, and MUC6 in AGS cells via CagA and/or NH₄⁺, but not E-cadherin.

Kataoka T, Okudela K, Matsumura M, et al.
A molecular pathological study of four cases of ciliated muconodular papillary tumors of the lung.
Pathol Int. 2018; 68(6):353-358 [PubMed] Related Publications
Ciliated muconodular papillary tumors (CMPTs) are a recently categorized benign or low-grade malignant neoplasm that develops in the peripheral lung. Only about 40 cases have been reported to date, and the clinicopathological characteristics have yet to be defined in detail. Here, we present four cases of CMPTs with a focus on their immunohistochemical profiles and driver gene mutations. These tumors were a papillary proliferation of a mixture of ciliated, mucous, and basal cells located in the peripheral lung. Ciliated, mucous and basal cells were positive for TTF-1 when using the clone SPT24, but negative for HNF-4α. Basal cells were positive for p40. Mucous cells in some tumors were positive for MUC5AC and MUC6. The Ki-67 index was less than 5%, and strong expression of p53 was not detected. Three of the four tumors had a BRAF (V600E) driver mutation, an EGFR (del E746-T751/S752V) driver mutation, or driver mutations in both EGFR (E709G) and KRAS (G12V). These mutation types are rare for any histological type of lung cancer. The present results confirmed that CMPT is a neoplasm with immunohistochemical features and driver gene mutations that are distinct from those of common lung tumors.

Matsuo Y, Yamamoto H, Sato Y, et al.
GNAS-mutated carcinoma arising from gastric foveolar metaplasia in the duodenum after 9 years of observation.
Clin J Gastroenterol. 2018; 11(5):391-395 [PubMed] Related Publications
This case involved an 80-year-old man. Screening with esophagogastroduodenoscopy (EGD) in 2004 revealed Brunner's gland hyperplasia (BGH), 5 mm in size, in the duodenal bulb. The size of the lesion increased and its shape has changed since then, as detected in subsequent EGDs. The lesion had increased in size to 15 mm with a depression and biopsy specimens revealed an adenocarcinoma. The patient underwent endoscopic mucosal resection. Histopathological assessments indicated an adenocarcinoma arising from gastric foveolar metaplasia (GFM) adjacent to BGH. BGH stained positive for MUC6, and GFM and the adenocarcinoma stained positive for MUC5AC. Mutations of the GNAS gene were not detected in the GFM biopsied in 2007. On the other hand, common GNAS mutations (R201H) were detected in GFM and the adenocarcinoma in the endoscopically resected specimen in 2013. Moreover, mutant allele frequencies were higher in the carcinoma than in GFM. The patient remains disease-free for 4 years after endoscopic treatment. This case report further supports the notion that GFM may be a precursor lesion in the process of GNAS-mutated, gastric-type duodenal carcinogenesis.

Osteikoetxea X, Benke M, Rodriguez M, et al.
Detection and proteomic characterization of extracellular vesicles in human pancreatic juice.
Biochem Biophys Res Commun. 2018; 499(1):37-43 [PubMed] Related Publications
AIMS: The prognosis of patients with pancreatic cancer has remained virtually unchanged with a high mortality rate compared to other types of cancers. An earlier detection would provide a time window of opportunity for treatment and prevention of deaths. In the present study we investigated extracellular vesicle (EV)-associated potential biomarkers for pancreatic cancer by directly assessing EV size-based subpopulations in pancreatic juice samples of patients with chronic pancreatitis or pancreatic cancer. In addition, we also studied blood plasma and pancreatic cancer cell line-derived EVs.
METHODS: Comparative proteomic analysis was performed of 102 EV preparations from human pancreatic juices, blood, and pancreatic cancer cell lines Capan-1 and MIA PaCa-2. EV preparations were also characterized by electron microscopy, tunable resistive pulse sensing, and flow cytometry.
RESULTS: Here we describe the presence of EVs in human pancreatic juice samples. Pancreatic juice EV-associated proteins that we identified as possible candidate markers for pancreatic cancer included mucins, such as MUC1, MUC4, MUC5AC, MUC6 and MUC16, CFTR, and MDR1 proteins. These candidate biomarkers could also be detected by flow cytometry in EVs found in pancreatic juice and those secreted by pancreatic cancer cell lines.
CONCLUSIONS: Together our data show that detection and characterization of EVs directly in pancreatic juice is feasible and may prove to be a valuable source of potential biomarkers of pancreatic cancer.

Basturk O, Berger MF, Yamaguchi H, et al.
Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma.
Mod Pathol. 2017; 30(12):1760-1772 [PubMed] Related Publications
Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2 fusions (FGFR2-CEP55, FGFR2-SASS6, DISP1-FGFR2, FGFR2-TXLNA, and FGFR2-VCL) and 1/18 (5.5%) had STRN-ALK fusion. Intraductal tubulopapillary neoplasm is a distinct clinicopathologic entity in the pancreas. Although its intraductal nature and some clinicopathologic features resemble those of intraductal papillary mucinous neoplasm, our results suggest that intraductal tubulopapillary neoplasm has distinguishing genetic characteristics. Some of these mutated genes are potentially targetable. Future functional studies will be needed to determine the consequences of these gene alterations.

Niv Y, Ho SB, Fass R, Rokkas T
Mucin Expression in the Esophageal Malignant and Pre-malignant States: A Systematic Review and Meta-analysis.
J Clin Gastroenterol. 2018; 52(2):91-96 [PubMed] Related Publications
BACKGROUND: Mucins are heavily glycosylated glycoproteins, synthesized by mucosal surfaces and have an important role in healthy state and malignant diseases. Change in mucins synthesis or secretion may be primary event or secondary to inflammation or carcinogenesis.
AIM: The aim of this study is to assess the current knowledge about mucin expression in esophageal lesions, and to establish a role for different mucin expressions as prognostic markers.
METHOD: English Medical literature searches were conducted for "mucin" and "esophagus." Observational studies were included. Meta-analysis was performed using comprehensive meta-analysis software. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated.
RESULTS: In the random-effect model, mucin expression was significantly higher in esophageal lesions than in normal esophageal mucosa with OR=5.456 (95% CI, 1.883-15.807, P=0.002). Measure of heterogeneity, demonstrated in the included studies, was high: Q=287.501, df (Q)=44.00, P<0.0001, I=84.696%. There is a gradient of mucin expression and complexity in esophageal premalignant to malignant lesions, lower in Barrett's mucosa with low grade dysplasia (LGD), increased in high grade dysplasia (HGD), and highest in esophageal adenocarcinoma (EAC). MUC2, MUC3, MUC5AC, and MUC6 expression was higher in EAC than HGD, and higher in HGD than in LGD mucosa. The opposite was found for MUC1 and MUC4.
CONCLUSION: Increased expression of certain mucin genes in esophageal mucosa may be further studied as a potential diagnostic tool, and this may add important information in the surveillance of Barrett's esophagus.

Duruisseaux M, Antoine M, Rabbe N, et al.
Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers.
Lung Cancer. 2017; 109:92-100 [PubMed] Related Publications
OBJECTIVES: To evaluate MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression in invasive lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA) of the lung, and the impact of oncogenic drivers.
MATERIALS AND METHODS: MUC1, MUC2, MUC5B, MUC5AC, MUC6, TTF1 and Hnf4α immunohistochemistry was performed on surgical samples from 52 patients with IMA (n=25) or LPA (n=27). We searched for EGFR, KRAS, BRAF, and HER2 mutations and ALK, ROS1, and NRG1 rearrangements.
RESULTS: MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression was detected in tumor cells in 77%, 2%, 63%, 36%, and 21% of cases, respectively. MUC1 was significantly more overexpressed in LPA. MUC5B, MUC5AC, and MUC6 were typically detected in goblet cells and overexpressed in IMA. Hnf4α-positive IMA (n=11) were TTF1-negative and typically did not expressed MUC1 and expressed MUC5AC and MUC6. Hnf4α-negative IMA (n=14) showed a reverse profile of mucins expression, with MUC1 expression and a lack of MUC5AC and MUC6 expression. EGFR-positive status was significantly associated with LPA, MUC1 expression, and no MUC5B, MUC5AC, or MUC6 expression. KRAS-positive status was significantly associated with IMA and MUC5B and MUC5AC expression.
CONCLUSIONS: LPA and IMA exhibit specific mucin expression profiles, with MUC1 being associated with LPA, while MUC5B, MUC5AC, and MUC6 were associated with IMA. Hnf4α expression and EGFR and KRAS mutations may play a role in mucin expression profiles of these lung adenocarcinoma subtypes.

Giraldi L, Michelazzo MB, Arzani D, et al.
MUC1, MUC5AC, and MUC6 polymorphisms, Helicobacter pylori infection, and gastric cancer: a systematic review and meta-analysis.
Eur J Cancer Prev. 2018; 27(4):323-330 [PubMed] Related Publications
The risk of Helicobacter pylori (HP) infection, as well as gastric cancer (GC), in association with genetic polymorphisms of gene encoding for mucins, has been investigated with contradictory results. We carried out this systematic review and meta-analysis to summarize the relationship between MUC1, MUC5AC, and MUC6 polymorphisms and HP infection, as well as GC risk. We searched MEDLINE, ISI Web of Science, Scopus bibliographic databases and the HuGE Navigator database. Odds ratios (ORs) and 95% confidence interval (CI) were calculated to assess the association between the genetic polymorphisms, and HP/GC risk. A random-effect model was used to calculate the pooled ORs, overall and by ethnicity. Twenty-one studies were included, of which five on HP and 18 on GC, of which two were in common. The meta-analysis of 10 studies on the MUC1 rs4072037 polymorphism and GC risk reported an OR of 0.66 (95% CI: 0.57-0.78) for the dominant model (AG/GG vs. AA). When stratifying for ethnicity, an OR of 0.73 (95% CI: 0.62-0.86) was reported for the Asian population and an OR of 0.48 (95% CI: 0.38-0.61) was reported for the White population. Our study confirms the protective effect of MUC1 rs4072037 polymorphism on the risk of GC under the dominant model. Further studies reporting information on HP status in cases and controls would be required to evaluate whether the protective effect of MUC1 protein might be attributable to a protective effect towards the HP infection, or through different mechanisms.

Xiong ZF, Shi J, Fu ZH, et al.
Phenotypic classification of gastric signet ring cell carcinoma and its relationship with K-ras mutation.
Genet Mol Res. 2017; 16(2) [PubMed] Related Publications
We aimed to analyze gastric signet ring cell (SRC) carcinoma subtypes by investigating gastric and intestinal phenotypic marker expression, and explore the relationship between phenotype and K-ras mutation. Immunohistochemistry was performed on 163 SRC carcinoma patient specimens to detect gastric (MUC1, MUC5AC, and MUC6) and intestinal (MUC2 and CDX2) phenotypic markers, and tumors were classified into gastric (G), intestinal (I), and gastrointestinal (GI) phenotypes. DNA was extracted from the formalin-fixed, paraffin-embedded tumor samples, and K-ras mutations in codons 12, 13, and 61 were identified using polymerase chain reaction-based direct DNA sequencing. G, GI, and I phenotypes were observed in 63 (38.6%), 71 (43.5%), and 29 cases (17.8%), respectively. Expression of MUC2 was significantly associated with invasion depth and lymph node metastasis (P = 0.001 and 0.002, respectively), whereas that of CDX2 significantly corresponded to tumor size and submucosal invasion (P = 0.004 and 0.001, respectively). MUC5AC expression was inversely associated with gastric wall invasion (P = 0.001). Intestinal phenotypic marker expression was positively associated with gastric wall invasion and lymph node metastasis. K-ras mutations, all of which were in codon 12, were detected in 20 (12.27%) tumors, were significantly associated with the I phenotype, and exhibited an inverse relationship with MUC5AC and MUC6 expression. I-phenotype SRC carcinomas should be distinguished from those of the G phenotype because of their increased malignancy regarding invasion and metastasis, and higher K-ras aberration rate. The different K-ras mutation frequencies observed imply distinct genetic mechanisms in the carcinogenesis of I- and G-phenotype gastric SRC carcinomas.

Kannan A, Hertweck KL, Philley JV, et al.
Genetic Mutation and Exosome Signature of Human Papilloma Virus Associated Oropharyngeal Cancer.
Sci Rep. 2017; 7:46102 [PubMed] Free Access to Full Article Related Publications
Human papilloma virus-16 (HPV-16) associated oropharyngeal cancer (HPVOPC) is increasing alarmingly in the United States. We performed whole genome sequencing of a 44 year old, male HPVOPC subject diagnosed with moderately differentiated tonsillar carcinoma. We identified new somatic mutation in MUC16 (A.k.a. CA-125), MUC12, MUC4, MUC6, MUC2, SIRPA, HLA-DRB1, HLA-A and HLA-B molecules. Increased protein expression of MUC16, SIRPA and decreased expression of HLA-DRB1 was further demonstrated in this HPVOPC subject and an additional set of 15 HPVOPC cases. Copy number gain (3 copies) was also observed for MUC2, MUC4, MUC6 and SIRPA. Enhanced expression of MUC16, SIRPA and HPV-16-E7 protein was detectable in the circulating exosomes of numerous HPVOPC subjects. Treatment of non-tumorigenic mammary epithelial cells with exosomes derived from aggressive HPVOPC cells harboring MUC16, SIRPA and HPV-16-E7 proteins augmented invasion and induced epithelial to mesenchymal transition (EMT) accompanied by an increased expression ratio of the EMT markers Vimentin/E-cadherin. Exosome based screening of key HPVOPC associated molecules could be beneficial for early cancer diagnosis, monitoring and surveillance.

Toba T, Inoshita N, Kaise M, et al.
Clinicopathological features of superficial non-ampurally duodenal epithelial tumor; gastric phenotype of histology correlates to higher malignant potency.
J Gastroenterol. 2018; 53(1):64-70 [PubMed] Related Publications
BACKGROUND: Superficial non-ampullary duodenal epithelial tumors (SNADETs) are relatively rare, but they are now being detected more frequently due to advances in endoscopic technology. Nevertheless, the pathological nature of SNADETs remains unclear and a management strategy for these tumors has not been established.
METHODS: To elucidate the clinicopathological features, we conducted a retrospective analysis of 138 endoscopically resected SNADETs. Lesions were classified into two groups by histological grade according to the Vienna classification: category 3 (71 lesions, 51.4%) and category 4/5 (67 lesions, 48.6%).
RESULTS: Compared with category 3 lesions, category 4/5 lesions were significantly more common in elderly patients (p < 0.001) and had a significantly larger tumor diameter (p = 0.001). Immunohistochemical analysis showed that category 4/5 lesions expressed MUC5AC (p = 0.002), MUC6 (p < 0.001), and p53 (p = 0.003) significantly more frequently and expressed CD10 (p = 0.002) and CDX2 (p = 0.029) significantly less frequently. Multivariate regression analysis showed that advanced age (p < 0.001), MUC6 expression (p = 0.001), and p53 expression (p = 0.004) were independent risk factors for a classification of category 4/5. In addition, advanced age (p = 0.010) and MUC5AC expression (p = 0.011) were identified as risk factors for lesions classified as category 4.2 (noninvasive carcinoma) or higher. All category 5 lesions expressed MUC5AC.
CONCLUSIONS: The gastric phenotype of MUC5AC and MUC6 may be linked to the malignant potential of SNADETs.

Xu MD, Liu SL, Feng YZ, et al.
Genomic characteristics of pancreatic squamous cell carcinoma, an investigation by using high throughput sequencing after in-solution hybrid capture.
Oncotarget. 2017; 8(9):14620-14635 [PubMed] Free Access to Full Article Related Publications
Squamous cell carcinoma (SCC) of pancreas is a rare histotype of pancreatic ductal carcinoma which is distinct from pancreatic adenocarcinoma (AC). Although there are standard treatments for pancreatic AC, no precise therapies exist for pancreatic SCC. Here, we screened 1033 cases of pancreatic cancer and identified 2 cases of pure SCC, which were pathologically diagnosed on the basis of finding definite intercellular bridges and/or focal keratin peal formation in the tumor cells. Immunohistochemistry assay confirmed the positive expression of CK5/6 and p63 in pancreatic SCC. To verify the genomic characteristics of pancreatic SCC, we employed in-solution hybrid capture targeting 137 cancer-related genes accompanied by high throughput sequencing (HTS) to compare the different genetic variants in SCC and AC of pancreas. We compared the genetic alterations of known biomarkers of pancreatic adenocarcinoma in different pancreatic cancer tissues, and identified nine mutated genes in SCC of pancreas: C7orf70, DNHD1, KPRP, MDM4, MUC6, OR51Q1, PTPRD, TCF4, TET2, and nine genes (ABCB1, CSF1R, CYP2C18, FBXW7, ITPA, KIAA0748, SOD2, SULT1A2, ZNF142) that are mutated in pancreatic AC. This study may have taken one step forward on the discovery of potential biomarkers for the targeted treatment of SCC of the pancreas.

Hida R, Yamamoto H, Hirahashi M, et al.
Duodenal Neoplasms of Gastric Phenotype: An Immunohistochemical and Genetic Study With a Practical Approach to the Classification.
Am J Surg Pathol. 2017; 41(3):343-353 [PubMed] Related Publications
Duodenal neoplasm of gastric phenotype (DNGP) is very rare, and details of its histopathologic, genetic, and biological features are still unclear. Frequent gene mutations in GNAS, KRAS, and APC have been reported in pyloric gland adenomas and fundic gland-type neoplasms (initially reported as low-grade adenocarcinomas) of the stomach. Here we retrospectively analyzed 16 cases of extra-ampullary DNGP (benign to malignant), and we examined the mucin immunoprofile and oncogene mutations (GNAS, KRAS, APC, BRAF, and CTNNB1). The 16 DNGPs were histologically classified into adenomas (5 pyloric gland adenomas and 2 foveolar-type adenomas), neoplasms of uncertain malignant potential (NUMPs, n=6), and invasive adenocarcinomas (n=3). NUMPs consisted of slightly atypical epithelial cells with pale, eosinophilic, or basophilic cytoplasm growing in an anastomosing or branching glandular pattern, often with expansive submucosal extension. In contrast to invasive adenocarcinomas, NUMPs lacked significant nuclear irregularity, desmoplastic stromal reaction, lymphovascular invasion, and metastasis; their features were reminiscent of fundic gland-type neoplasms of the stomach. Immunophenotypically, most of NUMPs were predominantly positive for MUC6 with variable expressions of pepsinogen-I, HKATPase, human gastric mucin, and MUC5AC. Molecular analyses revealed the gene mutations of GNAS in 6 (38%) of 16 DNGPs (4 [57%] adenomas, 1 [16%] NUMP, and 1 [33%] invasive adenocarcinoma) and APC in 4 of 15 (27%) DNGPs: no adenomas, 2 (33%) NUMPs, and 2 (67%) invasive adenocarcinomas. BRAF mutation was present in only 1 (16%) NUMP, and KRAS and CTNNB1 mutations were absent. In conclusion, gastric-phenotype adenomas and NUMPs of the duodenum are similar to their counterparts of the stomach, in terms of histologic, genetic, and clinicopathologic features. We propose the term "NUMP" as an intermediate category between adenoma and definitely invasive adenocarcinoma. Our findings may provide novel insights into the classification of undescribed but distinctive duodenal tumors showing similarity to gastric-phenotype neoplasms of the stomach.

Yamaguchi J, Mino-Kenudson M, Liss AS, et al.
Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice.
Gastroenterology. 2016; 151(6):1232-1244.e10 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: Little is known about the origin of pancreatic intraductal papillary mucinous neoplasms (IPMN). Pancreatic duct glands (PDGs) are gland-like outpouches budding off the main pancreatic ducts that function as a progenitor niche for the ductal epithelium; they express gastric mucins and have characteristics of side-branch IPMNs. We investigated whether PDGs are a precursor compartment for IPMNs and the role of Trefoil factor family 2 (TFF2)-a protein expressed by PDGs and the gastric mucosa that are involved in epithelial repair and tumor suppression.
METHODS: We obtained pancreatectomy specimens from 20 patients with chronic pancreatitis, 13 with low-grade side-branch IPMNs, and 15 patients with PDAC; histologically normal pancreata were used as controls (n = 18). Samples were analyzed by immunohistochemistry to detect TFF1 and TFF2 and cell proliferation. We performed mitochondrial DNA mutational mapping studies to determine the cell lineage and fate of PDG cells. Pdx1-Cre;LSL-KRAS
RESULTS: Histologic analysis of human samples revealed gastric-type IPMN to comprise 2 molecularly distinct layers: a basal crypt segment that expressed TFF2 and overlying papillary projections. Proliferation occurred predominantly in the PDG-containing basal segments. Mitochondrial mutation mapping revealed a 97% match between the profiles of proliferating PDG cells and their overlying nonproliferative IPMN cells. In contrast to KC mice, 2-month-old KC/Tff2
CONCLUSIONS: In histologic analyses of human IPMNs, we found PDGs to form the basal segment and possibly serve as a progenitor compartment. TFF2 has tumor-suppressor activity in the mouse pancreas and prevents formation of mucinous neoplasms.

Basturk O, Chung SM, Hruban RH, et al.
Distinct pathways of pathogenesis of intraductal oncocytic papillary neoplasms and intraductal papillary mucinous neoplasms of the pancreas.
Virchows Arch. 2016; 469(5):523-532 [PubMed] Free Access to Full Article Related Publications
Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is classified as a variant of intraductal papillary mucinous neoplasm (IPMN) in the WHO guidelines. However, the neoplastic cells of IOPNs are unique, with distinctive architecture/oncocytic cytoplasm. Although molecular/immunohistochemical features of other IPMN variants have been extensively studied, those of IOPNs have not been well characterized. Expression profile of antibodies associated with genetic alterations previously described for ductal adenocarcinomas (DAs) and IPMNs (SMAD4/β-catenin/p53/mesothelin/claudin-4) as well as antibodies to mucins and differentiation markers [MUC1/MUC2/MUC5AC/MUC6/CDX2/hepatocyte paraffin-1 (HepPar-1)] was investigated in 24 IOPNs and 22 IPMNs to assess the similarities/differences between these tumors. Expression of mesothelin and claudin-4 was dissimilar between these tumor types: A higher proportion of IOPNs labeled with mesothelin [21/24 (87.5 %) of IOPNs, 6/22 (27 %) of IPMNs, p < 0.001], while the reverse was true for claudin-4 [2/23 (9 %) of IOPNs, 9/22 (41 %) of IPMNs, p = 0.01]. The results of immunolabeling for SMAD4/β-catenin/p53 were similar in both: None of the cases showed SMAD4 loss in the intraductal components, and only 1/21 (5 %) of IOPNs and 2/22 (9 %) of IPMNs revealed abnormal β-catenin expression (p = 0.49). Nuclear p53 accumulation was seen mostly in architecturally complex/high-grade dysplasia areas in both. Immunolabeling for MUC proteins showed that almost all lesions expressed MUC5AC. Twelve of the 24 (50 %) IOPNs and 6/22 (27 %) of IPMNs (p = 0.11) labeled for MUC1, whereas 7/24 (29 %) of IOPNs and 10/22 (45 %) of IPMNs labeled for MUC2 (p = 0.25). MUC6 was expressed in 8/9 (89 %) of IOPNs (strong) and 6/21 (29 %) of IPMNs (weak) (p = 0.002). Fourteen of the 23 (61 %) IOPNs and 4/22 (18 %) of IPMNs labeled for HepPar-1 (p = 0.003). These results show that IOPNs have distinct immunoprofile and provide support for the proposition that IOPN is a distinct entity developing through a mechanism different from other pancreatic ductal neoplasms.

Imai T, Oue N, Nishioka M, et al.
Overexpression of KIF11 in Gastric Cancer with Intestinal Mucin Phenotype.
Pathobiology. 2017; 84(1):16-24 [PubMed] Related Publications
OBJECTIVE: Gastric cancer (GC) is one of the most common human cancers. A useful method of gastric cancer stem cell (CSC) characterization is spheroid colony formation. Previously, we reported that KIF11 expression is >2-fold in spheroid-body-forming GC cells compared with parental cells. Here, we analyzed the expression and distribution of KIF11 in human GC by immunohistochemistry.
METHODS: Expression of KIF11 in 165 GC cases was determined using immunohistochemistry. For mucin phenotypic expression analysis of GC, immunostaining of MUC5AC, MUC6, MUC2 and CD10 was evaluated. RNA interference was used to inhibit KIF11 expression in GC cell lines.
RESULTS: In total, 119 of 165 GC cases (72%) were positive for KIF11. Expression of KIF11 was not associated with any clinicopathologic characteristics; however, it was observed frequently in GC exhibiting an intestinal phenotype. Both the number and size of spheres formed by MKN-74 cells were significantly reduced following transfection of KIF11-targeting siRNA compared with negative-control siRNA. Furthermore, levels of phosphorylated Erk1/2 were lower in KIF11 siRNA-transfected cells than with negative-control siRNA-transfected cells.
CONCLUSION: These results indicate that KIF11 is involved in intestinal mucin phenotype GC.

Sierzega M, Młynarski D, Tomaszewska R, Kulig J
Semiquantitative immunohistochemistry for mucin (MUC1, MUC2, MUC3, MUC4, MUC5AC, and MUC6) profiling of pancreatic ductal cell adenocarcinoma improves diagnostic and prognostic performance.
Histopathology. 2016; 69(4):582-91 [PubMed] Related Publications
AIMS: Mucin (MUC) glycoproteins are involved in various steps of the carcinogenesis and progression of human malignancies. The aim of this study was to verify whether semiquantitative evaluation of MUC staining by immunohistochemistry may help to differentiate pancreatic ductal cell adenocarcinoma (PDAC) from chronic pancreatitis and normal pancreas.
METHODS AND RESULTS: Mucin expression was examined by immunohistochemistry in surgical specimens resected from 101 patients with PDAC and 33 with chronic pancreatitis, and in 40 normal pancreatic tissue specimens. A quickscore (QS, range 0-300) was calculated by multiplying staining intensity by the percentage of positive cells. A diagnostic model was developed for MUC QS (MUC1, MUC2, MUC3, MUC4, MUC5AC, and MUC6), based on a receiver operating characteristic (ROC) curve and logistic regression analysis. Median QS values for MUC1 and MUC5AC were significantly higher for PDAC, whereas patients with non-malignant tissues had higher values for MUC3 and MUC6. The area under the curve for the ROC curve derived from the diagnostic model including MUC3, MUC5AC and MUC6 was 0.96 [95% confidence interval (CI) 0.91-0.98], with 85% sensitivity and 94% specificity. Median QS values for MUC2 were significantly higher in patients with less advanced tumours, whereas venous invasion was associated with a lower QS for MUC6. Moreover, multivariate survival analysis revealed that low MUC6 expression was a negative prognostic factor, with a hazard ratio of 1.73 (95% CI 1.07-2.81).
CONCLUSIONS: The three-MUC diagnostic model (MUC3, MUC5AC, and MUC6) showed an excellent ability to discriminate pancreatic cancer from non-malignant tissues, and yielded information that may prove useful for the development of clinical applications.

Pivovarcikova K, Peckova K, Martinek P, et al.
"Mucin"-secreting papillary renal cell carcinoma: clinicopathological, immunohistochemical, and molecular genetic analysis of seven cases.
Virchows Arch. 2016; 469(1):71-80 [PubMed] Related Publications
Mucin and mucin-like material are features of mucinous tubular and spindle renal cell carcinoma (MTS RCC) but are rarely seen in papillary renal cell carcinoma (PRCC). We reviewed 1311 PRCC and identified 7 tumors containing extracellular and/or intracellular mucinous/mucin-like material (labeled as PRCCM). We analyzed these using morphological, histochemical, immunohistochemical, and molecular genetic methods (arrayCGH, FISH). Clinical data were available for six of the seven patients (five males and one female, age range 61-78 years). Follow-up was available for four patients (2-4 years); one patient died of widespread metastases. Tumor size ranged from 3 to 5 cm (mean 3.8). Of all cases, histological architecture showed a predominantly papillary pattern. Mucin or mucin-like was extracellular in one, intracellular in three, and both intra/extracellular in three cases. All tumors were positive for AMACR, vimentin, and OSCAR, while CK7 was positive in four. Mucicarmine stain was positive in all cases, PAS in six and Alcian blue in three cases. Five tumors were positive for MUC 1, but none were positive for MUC 2, MUC 4, or MUC 6. In only four cases, genetic analysis could be performed. Gain of chromosomes 7 and 17 was found in two cases; gain of 17 only was found in one case. Loss of heterozygosity of 3p was found in one case together with polysomy of chromosomes 7 and 17. No abnormalities of VHL, fumarate dehydrogenase, and TFE3 genes were detected. We conclude that PRCCM is a rare but challenging subtype of RCC that deserves to be further studied. In all the tumors, the mucin-like material was found in those stained with mucicarmin, but other conventional and immunohistochemical stains did not reveal consistent features of a single mucin. The molecular-genetic profile of these tumors was most consistent with that of typical papillary RCC, although one case had mixed genetic features of papillary and clear RCC. PRCCM has metastatic potential, as evidenced by one case with widespread metastases. It remains to be determined whether PRCCM represents a unique tumor subtype, deserving to be distinguished from other subtypes of PRCC.

Chlumská A, Waloschek T, Mukenšnabl P, et al.
Pyloric gland adenoma: a histologic, immunohistochemical and molecular genetic study of 23 cases.
Cesk Patol. 2015; 51(3):137-43 [PubMed] Related Publications
Pyloric gland adenoma is a rare neoplasm with a gastric epithelial differentiation. We report 23 cases of pyloric gland adenoma in older persons, with a mean age of 74 years (range 52 - 87 years). They occurred in the esophagus (3 cases), corporal gastric mucosa (7 cases), duodenum (10 cases), gallbladder (2 cases), and choledochus (one case). Histologically, they were characterized by closely packed pyloric gland-type tubules with a monolayer of cuboidal to low columnar epithelial cells containing basally located round nuclei, and a superficial layer of tall, columnar, foveolar-type epithelium. Immunohistochemically, most tumor glands expressed pyloric gland mucin MUC6, whereas MUC5AC was positive in superficial gastric foveolar epithelium, and in a minority of glands. In addition, scattered neuroendocrine cells positive for chromogranin A and/or synaptophysin were seen in all cases. In 3 cases (two cases in the gallbladder and one case in the esophagus), areas of intestinal metaplasia with CK20, CDX2, and MUC2 positivity were found. Focal low-grade dysplasia was found in five cases (21.7%), and diffuse high-grade dysplasia was seen in one adenoma (4.4%), i.e., 6 of 23 PGAs (26.1%) showed dysplastic features. In one esophageal case, an invasive adenocarcinoma was diagnosed. Scattered p53 positive cells were found in all cases. Their number was higher in lesions with low-grade dysplasia and it was substantially increased in adenoma with high-grade dysplasia and in adenocarcinoma. Our molecular genetic results indicate that pyloric gland adenomas neoplastic nature is associated with p53 accumulation, mutations in oncogenes GNAS, KRAS, CTTNB1 and tumor suppressor genes SMAD4, and TP53. Pyloric gland adenoma can evolve into dysplasia and adenocarcinoma.

Salomao M, Luna AM, Sepulveda JL, Sepulveda AR
Mutational analysis by next generation sequencing of gastric type dysplasia occurring in hyperplastic polyps of the stomach: Mutations in gastric hyperplastic polyps.
Exp Mol Pathol. 2015; 99(3):468-73 [PubMed] Related Publications
UNLABELLED: Gastric hyperplastic polyps (GHP) are the most common type of polyps occurring in the stomach. Although GHP are broadly interpreted as benign lesions, they may progress to dysplasia and adenocarcinoma.
OBJECTIVE: In this study, we aimed to identify genomic mutations that characterize and may drive malignant transformation in GHP by using next-generation sequencing. Eight GHP (2 with dysplasia, 1 indefinite for dysplasia and 5 without dysplasia) were studied. Only large polyps (>1cm) with gastric differentiation were included in this study, while adenomatous polyps (intestinal-type) were excluded. Immunohistochemistry for MUC2, MUC5A, MUC6, CDX2, p53, and Ki67 was performed. DNA was extracted from formalin-fixed paraffin-embedded sections and sequenced for the detection of somatic mutations. Multiplex sequencing was done with the TrueSeq Amplicon Cancer Panel in the MiSeq platform. Variant annotation and visualization were performed using NextGENe (SoftGenetics) software. No pathogenic mutations were detected in GHP without dysplasia. TP53 gene mutations were the most common alteration in dysplastic GHP (2 of 2 dysplastic cases). PIK3CA mutation was identified in a GHP with pyloric-type dysplasia, whereas foveolar-type dysplasia carried TP53 mutations. In conclusion, TP53 gene mutations are a common alteration in the early dysplastic stage during malignant transformation of GHP. GHP with dysplasia may show dual differentiation. In our study, pyloric-type dysplasia was associated with a PIK3CA alteration whereas foveolar dysplasia carried TP53 mutations. The identification of carcinoma-associated mutations in large GHP provides additional evidence of their neoplastic potential and emphasizes the need for their complete resection and follow-up.

Bittoni A, Piva F, Santoni M, et al.
KRAS mutation status is associated with specific pattern of genes expression in pancreatic adenocarcinoma.
Future Oncol. 2015; 11(13):1905-17 [PubMed] Related Publications
AIMS: To evaluate potential differences at a molecular level between KRAS mutant tumors (MT) and KRAS wild-type (WT) pancreatic tumors and the biological and prognostic significance of different KRAS mutations.
MATERIALS & METHODS: Expression of a panel of 29 genes was analyzed in KRAS WT and MT tumors. Effects of KRAS mutation and gene expression levels were assessed on patients' survival.
RESULTS: MUC6 (p = 0.009), HGF (p = 0.011), VEGFR-2 (p = 0.020) and VEGFB (p = 0.026) were significantly more expressed and SMAD4 was less suppressed (p = 0.003) in WT KRAS. Contrariwise, SHH (p = 0.012) and IHH (p = 0.031) were more expressed in MT KRAS patients. No OS difference was found between WT and MT KRAS tumors.
CONCLUSION: KRAS mutation status seems to identify two different subtypes of pancreatic ductal adenocarcinoma with similar outcome but distinct molecular features and probably different therapeutic targets.

Vo DT, Nakayama T, Yamamoto H, et al.
Progression risk assessments of individual non-invasive gastric neoplasms by genomic copy-number profile and mucin phenotype.
BMC Med Genomics. 2015; 8:6 [PubMed] Free Access to Full Article Related Publications
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.

Garcia-Carracedo D, Yu CC, Akhavan N, et al.
Smad4 loss synergizes with TGFα overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis.
PLoS One. 2015; 10(3):e0120851 [PubMed] Free Access to Full Article Related Publications
AIMS: While overexpression of TGFα has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFα develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-β signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFα and TGF-β signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation.
METHODS: The MT-TGFα mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGFα;p48-Cre (STP). After TGFα overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFα, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (α-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR.
RESULTS: Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFα mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC.
CONCLUSION: We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer.

Kumagai R, Kohashi K, Takahashi S, et al.
Mucinous phenotype and CD10 expression of primary adenocarcinoma of the small intestine.
World J Gastroenterol. 2015; 21(9):2700-10 [PubMed] Free Access to Full Article Related Publications
AIM: To clarify the correlation with phenotypic expression, clinicopathological features, genetic alteration and microsatellite-instability status in small intestinal adenocarcinoma (SIA).
METHODS: The cases of 47 patients diagnosed with primary SIAs that were surgically resected at our institution in 1975-2005 were studied. We reviewed clinicopathological findings (age, gender, tumor size, gross appearance, histological morphologic type, invasion depth, lymphatic permeation, venous invasion, and lymph node metastasis), and the immunohistochemical expression of MUC5AC, MUC6, MUC2, CD10, and mismatch-repair (MMR) proteins (MLH1 and MSH2). We analyzed KRAS and BRAF gene mutations, and the microsatellite instability (MSI) status. The immunohistochemical staining of CD10, MUC2, MUC5AC and MUC6 was considered positive when distinct staining in > 5% of the adenocarcinoma cells was recorded. To evaluate of MMR protein expression, we used adjacent normal tissue including lymphoid follicles, inflammatory cells, and stromal cells as an internal positive control. Sections without nuclear staining in the tumor cells were considered to have lost the expression of the respective MMR protein.
RESULTS: There were 29 males and 18 females patients (mean age 59.9 years, range: 23-87 years). Tumors were located in the duodenum in 14 cases (30%), the jejunum in 21 cases (45%), and the ileum in 12 cases (25%). A phenotypic expression analysis revealed 20 MUC2-positive tumors (42.6%), 11 MUC5AC-positive (23.4%), 4 MUC6-positive (8.5%), and 7 CD10-positive (14.9%). The tumor sizes of the MUC2(+) tumors were significantly larger than those of the MUC2(-) tumors (mean, 5.7 ± 1.4 cm vs 4.7 ± 2.1 cm, P < 0.05). All three tumors with adenomatous component were positive for MUC2 (P < 0.05). Polypoid appearance was seen significantly more frequently in the CD10(+) group than in the CD10(-) group (P < 0.05). The tumor size was significantly larger in the CD10 (+) group than in the CD10(-) group (mean, 5.9 ± 1.4 cm vs 5.0 ± 2.1 cm, P < 0.05). Of 34 SIAs with successfully obtained MSI data, 4 were MSI-high. Of the 4 SIAs positive for both MUC5AC and MUC2, 3 showed MSI-H (75%) and 3 were mucinous adenocarcinoma (75%). KRAS mutations were detected in 4 SIAs. SIAs had KRAS mutation expressed only MUC2, but were negative for MUC5AC, MUC6 and CD10.
CONCLUSION: These findings suggest that the phenotypic expression of SIAs is correlated with their biological behavior, genetic alteration, and MSI status.

Shibahara H, Higashi M, Yokoyama S, et al.
A comprehensive expression analysis of mucins in appendiceal carcinoma in a multicenter study: MUC3 is a novel prognostic factor.
PLoS One. 2014; 9(12):e115613 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma.
METHODS: Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma.
RESULTS: The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p = 0.036); MUC2 with histological type (mucinous carcinoma, p<0.001), superficial invasion depth (p = 0.007), negative venous invasion (p = 0.003), and curative resection (p = 0.019); MUC3 with non-curative resection (p = 0.017); MUC5AC with histological type (mucinous carcinoma, p = 0.002), negative lymphatic invasion (p = 0.021), and negative venous invasion (p = 0.022); and MUC16 with positive lymph node metastasis (p = 0.035), positive venous invasion (p<0.05), and non-curative resection (p = 0.035). A poor prognosis was related to positive lymph node metastasis (p = 0.04), positive lymphatic invasion (p = 0.02), positive venous invasion (p<0.001), non-curative resection (p<0.001), and positive expression of MUC3 (p = 0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93-24.96, p = 0.003), non-curative resection (HR: 10.19, 95% CI: 3.05-34.07, p<0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13-10.03, p = 0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma.
CONCLUSIONS: Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery.

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