Predictive gene signatures: molecular markers distinguishing colon adenomatous polyp and carcinoma

Janice E. Drew; Andrew J. Farquharson; Claus Dieter Mayer; Hollie F. Vase; Philip J. Coates; Robert J. Steele; Francis A.  Carey

doi:10.1371/journal.pone.0113071

Predictive gene signatures: molecular markers distinguishing colon adenomatous polyp and carcinoma

Janice E. Drew, Andrew J. Farquharson, Claus Dieter Mayer, Hollie F. Vase, Philip J. Coates, Robert J. Steele, Francis A. Carey

The Rowett Institute of Nutrition and Health

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Abstract

Cancers exhibit abnormal molecular signatures associated with disease initiation and progression. Molecular signatures could improve cancer screening, detection, drug development and selection of appropriate drug therapies for individual patients. Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that cannot be captured using a single marker. This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay, the hCellMarkerPlex, to assess predictive gene signatures of normal, adenomatous polyp and carcinoma colon tissue using archived tissue bank material. The hCellMarkerPlex incorporates twenty-one gene markers: epithelial (EZR, KRT18, NOX1, SLC9A2), proliferation (PCNA, CCND1, MS4A12), differentiation (B4GANLT2, CDX1, CDX2), apoptotic (CASP3, NOX1, NTN1), fibroblast (FSP1, COL1A1), structural (ACTG2, CNN1, DES), gene transcription (HDAC1), stem cell (LGR5), endothelial (VWF) and mucin production (MUC2). Gene signatures distinguished normal, adenomatous polyp and carcinoma. Individual gene targets significantly contributing to molecular tissue types, classifier genes, were further characterised using real-time PCR, in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of MS4A12, LGR5 CDX2, NOX1 and SLC9A2 prior to development of carcinoma. Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays. This approach may be used to assist in objective classification of disease initiation, staging, progression and therapeutic responses using biopsy material.

Original language	English
Article number	0113071
Number of pages	20
Journal	PloS ONE
Volume	9
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0113071
Publication status	Published - 25 Nov 2014

Bibliographical note

Funding: This study was supported by the Scottish Government's Rural and Environment Science and Analytical Services Division Food, Land and People Programme GT403 (http://www.scotland.gov.uk/Topics/Research/About/EBAR/StrategicResearch/future-research-strategy/Themes), Scottish Universities Life Science Alliance Translational Biology Studentship 10/09, (http://www.sulsa.ac.uk/), NHS Grampian Endowment Fund 12/07 (http://www.nhsgrampian.co.uk/nhsgrampian/gra_display_hospital.jsp?pContentID=65&p_applic=CCC&p_service=Content.show&). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

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@article{9b2194201ab5471bb5f01cf12278a3a7,

title = "Predictive gene signatures: molecular markers distinguishing colon adenomatous polyp and carcinoma",

abstract = "Cancers exhibit abnormal molecular signatures associated with disease initiation and progression. Molecular signatures could improve cancer screening, detection, drug development and selection of appropriate drug therapies for individual patients. Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that cannot be captured using a single marker. This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay, the hCellMarkerPlex, to assess predictive gene signatures of normal, adenomatous polyp and carcinoma colon tissue using archived tissue bank material. The hCellMarkerPlex incorporates twenty-one gene markers: epithelial (EZR, KRT18, NOX1, SLC9A2), proliferation (PCNA, CCND1, MS4A12), differentiation (B4GANLT2, CDX1, CDX2), apoptotic (CASP3, NOX1, NTN1), fibroblast (FSP1, COL1A1), structural (ACTG2, CNN1, DES), gene transcription (HDAC1), stem cell (LGR5), endothelial (VWF) and mucin production (MUC2). Gene signatures distinguished normal, adenomatous polyp and carcinoma. Individual gene targets significantly contributing to molecular tissue types, classifier genes, were further characterised using real-time PCR, in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of MS4A12, LGR5 CDX2, NOX1 and SLC9A2 prior to development of carcinoma. Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays. This approach may be used to assist in objective classification of disease initiation, staging, progression and therapeutic responses using biopsy material.",

author = "Drew, {Janice E.} and Farquharson, {Andrew J.} and Mayer, {Claus Dieter} and Vase, {Hollie F.} and Coates, {Philip J.} and Steele, {Robert J.} and Carey, {Francis A.}",

note = "Funding: This study was supported by the Scottish Government's Rural and Environment Science and Analytical Services Division Food, Land and People Programme GT403 (http://www.scotland.gov.uk/Topics/Research/About/EBAR/StrategicResearch/future-research-strategy/Themes), Scottish Universities Life Science Alliance Translational Biology Studentship 10/09, (http://www.sulsa.ac.uk/), NHS Grampian Endowment Fund 12/07 (http://www.nhsgrampian.co.uk/nhsgrampian/gra_display_hospital.jsp?pContentID=65&p_applic=CCC&p_service=Content.show&). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. ",

year = "2014",

month = nov,

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doi = "10.1371/journal.pone.0113071",

language = "English",

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T2 - molecular markers distinguishing colon adenomatous polyp and carcinoma

AU - Drew, Janice E.

AU - Farquharson, Andrew J.

AU - Mayer, Claus Dieter

AU - Vase, Hollie F.

AU - Coates, Philip J.

AU - Steele, Robert J.

AU - Carey, Francis A.

N1 - Funding: This study was supported by the Scottish Government's Rural and Environment Science and Analytical Services Division Food, Land and People Programme GT403 (http://www.scotland.gov.uk/Topics/Research/About/EBAR/StrategicResearch/future-research-strategy/Themes), Scottish Universities Life Science Alliance Translational Biology Studentship 10/09, (http://www.sulsa.ac.uk/), NHS Grampian Endowment Fund 12/07 (http://www.nhsgrampian.co.uk/nhsgrampian/gra_display_hospital.jsp?pContentID=65&p_applic=CCC&p_service=Content.show&). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

PY - 2014/11/25

Y1 - 2014/11/25

N2 - Cancers exhibit abnormal molecular signatures associated with disease initiation and progression. Molecular signatures could improve cancer screening, detection, drug development and selection of appropriate drug therapies for individual patients. Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that cannot be captured using a single marker. This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay, the hCellMarkerPlex, to assess predictive gene signatures of normal, adenomatous polyp and carcinoma colon tissue using archived tissue bank material. The hCellMarkerPlex incorporates twenty-one gene markers: epithelial (EZR, KRT18, NOX1, SLC9A2), proliferation (PCNA, CCND1, MS4A12), differentiation (B4GANLT2, CDX1, CDX2), apoptotic (CASP3, NOX1, NTN1), fibroblast (FSP1, COL1A1), structural (ACTG2, CNN1, DES), gene transcription (HDAC1), stem cell (LGR5), endothelial (VWF) and mucin production (MUC2). Gene signatures distinguished normal, adenomatous polyp and carcinoma. Individual gene targets significantly contributing to molecular tissue types, classifier genes, were further characterised using real-time PCR, in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of MS4A12, LGR5 CDX2, NOX1 and SLC9A2 prior to development of carcinoma. Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays. This approach may be used to assist in objective classification of disease initiation, staging, progression and therapeutic responses using biopsy material.

AB - Cancers exhibit abnormal molecular signatures associated with disease initiation and progression. Molecular signatures could improve cancer screening, detection, drug development and selection of appropriate drug therapies for individual patients. Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that cannot be captured using a single marker. This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay, the hCellMarkerPlex, to assess predictive gene signatures of normal, adenomatous polyp and carcinoma colon tissue using archived tissue bank material. The hCellMarkerPlex incorporates twenty-one gene markers: epithelial (EZR, KRT18, NOX1, SLC9A2), proliferation (PCNA, CCND1, MS4A12), differentiation (B4GANLT2, CDX1, CDX2), apoptotic (CASP3, NOX1, NTN1), fibroblast (FSP1, COL1A1), structural (ACTG2, CNN1, DES), gene transcription (HDAC1), stem cell (LGR5), endothelial (VWF) and mucin production (MUC2). Gene signatures distinguished normal, adenomatous polyp and carcinoma. Individual gene targets significantly contributing to molecular tissue types, classifier genes, were further characterised using real-time PCR, in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of MS4A12, LGR5 CDX2, NOX1 and SLC9A2 prior to development of carcinoma. Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays. This approach may be used to assist in objective classification of disease initiation, staging, progression and therapeutic responses using biopsy material.

U2 - 10.1371/journal.pone.0113071

DO - 10.1371/journal.pone.0113071

M3 - Article

SN - 1932-6203

VL - 9

JO - PloS ONE

JF - PloS ONE

IS - 11

M1 - 0113071

ER -

Predictive gene signatures: molecular markers distinguishing colon adenomatous polyp and carcinoma

Abstract

Bibliographical note

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