Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours

Salto-Tellez, Manuel; Nga, Min‐En; Han, Hui; Wong, Alfred; Lee, C.K.; Anuar, Diyanah; Ng, S-B; Ho, Maria Yi; A, Wee; Chan, Yiong Huak; Soong, Richie

doi:10.1038/sj.bjc.6603551

Cited by 27 publications

(20 citation statements)

References 22 publications

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“…Three sets of ovarian cancer tissue microarrays containing three cores from 198 primary ovarian cancer cases, three sets of breast tissue microarrays containing three cores from 300 breast cancer cases, and one set of gastric tissue mircroarrays containing 142 gastric cancer cases were constructed as detailed in previous studies. 18,19 A 1.0-mm-diameter needle was used to punch a donor core from morphologically representative areas of a donor tissue block. The core was subsequently inserted into a recipient paraffin block using a MTA-1 Manual Tissue Arrayer (Beecher Instruments, WI).…”

Section: Methodsmentioning

confidence: 99%

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

Stewart¹,

James

McCluggage

et al. 2015

Modern Pathology

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The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers. Immunohistochemical analysis using a TMA platform revealed WLS overexpression in a subset of ovarian, gastric, and breast tumors; this overexpression was associated with poorer clinical outcomes in gastric cancer (P ¼ 0.025). In addition, a strong correlation was observed between WLS expression and human epidermal growth factor receptor 2 (HER2) overexpression. Indeed, 100% of HER2-positive intestinal gastric carcinomas, 100% of HER2-positive serous ovarian carcinomas, and 64% of HER2-positive breast carcinomas coexpressed WLS protein. Although HER2 protein expression or gene amplification is an established predictive biomarker for trastuzumab response in breast and gastric cancers, a significant proportion of HER2-positive tumors display resistance to trastuzumab, which may be in part explainable by a possible mechanistic link between WLS and HER2. Modern Pathology (2015) 28, 428-436; doi:10.1038/modpathol.2014 published online 26 September 2014 The molecular mechanisms controlling the maturation and secretion of WNT proteins in the cells responsible for their production are attracting considerable attention. Wntless (WLS) (also known as GPR177 and Evi) was recently discovered as a key modulator of WNT protein secretion. [1][2][3] This multipass transmembrane protein localizes to compartments of the secretory pathway including the Golgi apparatus, endosomes, and plasma membrane. WLS acts as a WNT cargo receptor, shuttling palmitoylated Wnts from the endoplasmic reticulum to the plasma membrane, and it is required for exocytosis of WNT proteins from the WNT-producing cells. 4 In contrast to most other components of the WNT signaling pathway, only a single WLS gene exists in vertebrate genomes. WLS appears to be required for the secretion of all WNT proteins in both the canonical and noncanonical WNT pathways. 5 Augustin et al 6 recently demonstrated that WLS is highly overexpressed in malignant astrocytomas, indicating that the aberrant release of canonical and noncanonical WNT is a potential driver of glioma tumorigenesis required for proliferation, survival, and migration of glioma cells. Their work raises the question of whether WLS has a similar role in other cancers known to have aberrant activation of WNT signaling, including ovarian, gastric, and breast cancers. [7][8][9][10][11][12][13][14][15]

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Section: Methodsmentioning

confidence: 99%

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

Stewart¹,

James

McCluggage

et al. 2015

Modern Pathology

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“…The TMA blocks were constructed as described previously. (28,29) Briefly, a 0.6-mm diameter needle was used to punch a donor core from morphologically representative areas of a donor paraffin-embedded tissue block. The core was then inserted into a recipient paraffin block using an ATA-100 tissue arrayer (Chemicon International, Temecula, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of neurone glial‐related cell adhesion molecule is an independent predictor of poor prognosis in advanced colorectal cancer

2011

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A downstream target of the Wnt pathway, neurone glial-related cell adhesion molecule (Nr-CAM) has recently been implicated in human cancer development. However, its role in colorectal cancer (CRC) pathobiology and clinical relevance remains unknown. In this study, we examined the clinical significance of Nr-CAM protein expression in a retrospective series of 428 CRCs using immunohistochemistry and tissue microarrays. Cox proportional hazards regression was used to calculate hazard ratios (HR) of mortality according to various clinicopathological features and molecular markers. All CRC samples were immunoreactive for Nr-CAM protein expression, compared to 10 ⁄ 245 (4%) matched normal tissue (P < 0.0001). Of 428 CRC samples, 97 (23%) showed Nr-CAM overexpression, which was significantly associated with nodal (P = 0.012) and distant (P = 0.039) metastasis, but not with extent of local invasion or tumor size. Additionally, Nr-CAM overexpression was associated with vascular invasion (P = 0.0029), p53 expression (P = 0.036), and peritoneal metastasis at diagnosis (P = 0.013). In a multivariate model adjusted for other clinicopathological predictors of survival, Nr-CAM overexpression correlated with a significant increase in disease-specific (HR 1.66; 95% confidence interval 1.11-2.47; P = 0.014) and overall mortality (HR 1.57; 95% confidence interval 1.07-2.30; P = 0.

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“…4,15,[28][29][30][31] Expression profiling of GIST has identified molecular signatures associated with survival or genotype. 32 In this study, we performed expression analysis comparing GISTs carrying KIT exon 11 deletions and GISTs without mutations in KIT exon 11.…”

Section: Kip1mentioning

confidence: 99%

Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis

Arne¹,

Kristiansson²,

Nerman³

et al. 2011

Intl Journal of Cancer

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In gastrointestinal stromal tumors (GISTs), KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profiles of GISTs carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Expression profiling was performed on nine tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analyzed by metaanalysis. Expression of CD133 (prominin-1) protein was examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in western Sweden. Survival analysis was performed on patients subjected to R0 resection (n 5 180) using the Cox proportional hazards model. Gene expression profiling, meta-analysis, and qPCR showed up regulation of CD133 in GISTs carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was more frequent in gastric GISTs (48%) than in small intestinal GISTs (4%). CD133 positivity was also more frequent in GISTs with KIT exon 11 mutations (41%) than in tumors with mutations in KIT exon 9, plateletderived growth factor receptor a (PDGFRA), or wild-type tumors (0-17%). Univariate survival analysis showed a significant correlation between the presence of CD133 protein and shorter overall survival (hazard ratio 5 2.23, p 5 0.027). Multivariate analysis showed that CD133 provided additional information on patient survival compared to age, sex, National Institutes of Health (NIH) risk group and mutational status. CD133 is expressed in a subset of predominantly gastric GISTs with KIT exon 11 mutations and poor prognosis.

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Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours

Cited by 27 publications

References 22 publications

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

Overexpression of neurone glial‐related cell adhesion molecule is an independent predictor of poor prognosis in advanced colorectal cancer

Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis

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