The Relative Distribution of Membranous and Cytoplasmic Met Is a Prognostic Indicator in Stage I and II Colon Cancer

Ginty, Fiona; Adak, Sudeshna; Can, Ali; Gerdes, Michael J.; Larsen, Melinda; Cline, Harvey; Filkins, Robert J.; Pang, Zhengyu; Li, Qing; Montalto, Michael

doi:10.1158/1078-0432.ccr-08-0180

Cited by 42 publications

(23 citation statements)

References 39 publications

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“…Recently, a new technology has been developed by GE Healthcare that allows for immunofluorescence (IF) of the same tissue section with more than 10 different antibodies serially (known as multiplex IF; ref. 18), which was used to confirm all of our results ( Figure 3, Supplemental Figure 3, and Supplemental Methods).…”

Section: Analysis Of CD Markers and Intermediate Filaments In Normal supporting

confidence: 57%

Taxonomy of breast cancer based on normal cell phenotype predicts outcome

Santagata¹,

Thakkar²,

Ergonul³

et al. 2014

J. Clin. Invest.

171

214

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Accurate classification is essential for understanding the pathophysiology of a disease and can inform therapeutic choices. For hematopoietic malignancies, a classification scheme based on the phenotypic similarity between tumor cells and normal cells has been successfully used to define tumor subtypes; however, use of normal cell types as a reference by which to classify solid tumors has not been widely emulated, in part due to more limited understanding of epithelial cell differentiation compared with hematopoiesis. To provide a better definition of the subtypes of epithelial cells comprising the breast epithelium, we performed a systematic analysis of a large set of breast epithelial markers in more than 15,000 normal breast cells, which identified 11 differentiation states for normal luminal cells. We then applied information from this analysis to classify human breast tumors based on normal cell types into 4 major subtypes, HR0-HR3, which were differentiated by vitamin D, androgen, and estrogen hormone receptor (HR) expression. Examination of 3,157 human breast tumors revealed that these HR subtypes were distinct from the current classification scheme, which is based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Patient outcomes were best when tumors expressed all 3 hormone receptors (subtype HR3) and worst when they expressed none of the receptors (subtype HR0). Together, these data provide an ontological classification scheme associated with patient survival differences and provides actionable insights for treating breast tumors.

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Section: Analysis Of CD Markers and Intermediate Filaments In Normal supporting

confidence: 57%

Taxonomy of breast cancer based on normal cell phenotype predicts outcome

Santagata¹,

Thakkar²,

Ergonul³

et al. 2014

J. Clin. Invest.

171

214

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“…25,67 Furthermore, previous studies have provided evidence for the prognostic value of MET protein expression in the early stages of carcinoma progression. 68,69 In this study the majority of patients had metastatic disease and they all received the appropriate chemotherapy although their access to EGFR-or VEGF-targeted therapy was not always based on molecular biomarker selection; therefore, the data reported herein highlight the value of MET expression in metastases as a biomarker that might be used to select advanced colorectal cancer patients who could benefit from targeted therapies.…”

Section: Discussionmentioning

confidence: 94%

Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

et al. 2013

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Metastasis is the main cause of mortality in patients with colorectal cancer. However, most of the targeted therapies and predictive molecular biomarkers were developed based mainly on primary tumors. The current study was conducted to determine the degree of discordance between potential predictive and/or prognostic molecular markers in primary colorectal tumors and corresponding metastases, as this could have an impact on the efficacy of targeted therapies in the advanced colorectal cancer. KRAS, PIK3CA and BRAF mutations were determined by Sanger sequencing and mutant-enriched polymerase chain reaction (PCR) assays in 83 paired samples, MET gene copy number by quantitative PCR in 59, MET expression by immunohistochemistry in 73 and nuclear and cytoplasmic expression of PTEN by immunohistochemistry in 78 and 71 pairs, respectively. A certain degree of discordance between primary tumors and corresponding metastases was demonstrated for all examined biomarkers except BRAF mutations. PIK3CA exon 9 mutations in primary tumors and loss of PTEN nuclear expression in metastases correlated with KRAS mutations. KRAS wild-type status in primary tumors was associated with loss of PTEN cytoplasmic expression and high gene copy number of MET. Survival and clinical data were available for 68 patients. The multiple regression analysis revealed that the right-sided tumor localization and overexpression of MET were associated with shorter overall survival.

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“…Pseudocolored, overlaid images were generated to visualize tissue architecture (Fig. 2E), and computational image analysis algorithms were used to generate segmentation masks for cellular and subcellular analysis of epithelial cells (16) (Figs. 1 and 2F).…”

Section: Resultsmentioning

confidence: 99%

Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue

Gerdes¹,

Sevinsky

Sood³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

643

761

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Limitations on the number of unique protein and DNA molecules that can be characterized microscopically in a single tissue specimen impede advances in understanding the biological basis of health and disease. Here we present a multiplexed fluorescence microscopy method (MxIF) for quantitative, single-cell, and subcellular characterization of multiple analytes in formalin-fixed paraffinembedded tissue. Chemical inactivation of fluorescent dyes after each image acquisition round allows reuse of common dyes in iterative staining and imaging cycles. The mild inactivation chemistry is compatible with total and phosphoprotein detection, as well as DNA FISH. Accurate computational registration of sequential images is achieved by aligning nuclear counterstain-derived fiducial points. Individual cells, plasma membrane, cytoplasm, nucleus, tumor, and stromal regions are segmented to achieve cellular and subcellular quantification of multiplexed targets. In a comparison of pathologist scoring of diaminobenzidine staining of serial sections and automated MxIF scoring of a single section, human epidermal growth factor receptor 2, estrogen receptor, p53, and androgen receptor staining by diaminobenzidine and MxIF methods yielded similar results. Single-cell staining patterns of 61 protein antigens by MxIF in 747 colorectal cancer subjects reveals extensive tumor heterogeneity, and cluster analysis of divergent signaling through ERK1/2, S6 kinase 1, and 4E binding protein 1 provides insights into the spatial organization of mechanistic target of rapamycin and MAPK signal transduction. Our results suggest MxIF should be broadly applicable to problems in the fields of basic biological research, drug discovery and development, and clinical diagnostics.cancer diagnostics | high-content cellular analysis | image analysis | mTOR | multiplexing

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The Relative Distribution of Membranous and Cytoplasmic Met Is a Prognostic Indicator in Stage I and II Colon Cancer

Cited by 42 publications

References 39 publications

Taxonomy of breast cancer based on normal cell phenotype predicts outcome

Taxonomy of breast cancer based on normal cell phenotype predicts outcome

Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer

Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue

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