APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling

Russell D. Petty (Lead / Corresponding author), Leslie M. Samuel, Graeme I. Murray, Graham MacDonald, Terrence O'Kelly, Malcolm Loudon, Norman Binnie, Emad Aly, Aileen McKinlay, Weiguang Wang, Fiona Gilbert, Scot Semple, Elaina S. R. Collie-Duguid (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    30 Citations (Scopus)

    Abstract

    BACKGROUND: 5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets.

    METHODS: Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified.

    RESULTS: APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent with APRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95%CI 1.48-26.32), p = 0.013].

    CONCLUSIONS: A combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.

    Original languageEnglish
    Article number434
    Number of pages11
    JournalBMC Cancer
    Volume9
    DOIs
    Publication statusPublished - 11 Dec 2009

    Fingerprint

    Gene Expression Profiling
    Fluorouracil
    Adenocarcinoma
    Biomarkers
    Radiotherapy
    Neoplasms
    Tumor Necrosis Factor Ligand Superfamily Member 13
    Gene Expression
    Cell Line
    Therapeutics
    Nuclear Family
    Transcriptome
    Colorectal Neoplasms
    Immunohistochemistry

    Keywords

    • Adenocarcinoma
    • Adult
    • Antineoplastic Agents
    • Colorectal Neoplasms
    • Drug Resistance, Neoplasm
    • Fluorouracil
    • Gene Expression
    • Gene Expression Profiling
    • Humans
    • Immunohistochemistry
    • Kaplan-Meier Estimate
    • Oligonucleotide Array Sequence Analysis
    • Tumor Markers, Biological
    • Tumor Necrosis Factor Ligand Superfamily Member 13

    Cite this

    Petty, R. D., Samuel, L. M., Murray, G. I., MacDonald, G., O'Kelly, T., Loudon, M., ... Collie-Duguid, E. S. R. (2009). APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling. BMC Cancer, 9, [434]. https://doi.org/10.1186/1471-2407-9-434
    Petty, Russell D. ; Samuel, Leslie M. ; Murray, Graeme I. ; MacDonald, Graham ; O'Kelly, Terrence ; Loudon, Malcolm ; Binnie, Norman ; Aly, Emad ; McKinlay, Aileen ; Wang, Weiguang ; Gilbert, Fiona ; Semple, Scot ; Collie-Duguid, Elaina S. R. / APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling. In: BMC Cancer. 2009 ; Vol. 9.
    @article{d6bbc2708f0f486f849d02612e9b5e9e,
    title = "APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling",
    abstract = "BACKGROUND: 5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets.METHODS: Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified.RESULTS: APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent with APRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95{\%}CI 1.48-26.32), p = 0.013].CONCLUSIONS: A combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.",
    keywords = "Adenocarcinoma, Adult, Antineoplastic Agents, Colorectal Neoplasms, Drug Resistance, Neoplasm, Fluorouracil, Gene Expression, Gene Expression Profiling, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Oligonucleotide Array Sequence Analysis, Tumor Markers, Biological, Tumor Necrosis Factor Ligand Superfamily Member 13",
    author = "Petty, {Russell D.} and Samuel, {Leslie M.} and Murray, {Graeme I.} and Graham MacDonald and Terrence O'Kelly and Malcolm Loudon and Norman Binnie and Emad Aly and Aileen McKinlay and Weiguang Wang and Fiona Gilbert and Scot Semple and Collie-Duguid, {Elaina S. R.}",
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    language = "English",
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    }

    Petty, RD, Samuel, LM, Murray, GI, MacDonald, G, O'Kelly, T, Loudon, M, Binnie, N, Aly, E, McKinlay, A, Wang, W, Gilbert, F, Semple, S & Collie-Duguid, ESR 2009, 'APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling', BMC Cancer, vol. 9, 434. https://doi.org/10.1186/1471-2407-9-434

    APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling. / Petty, Russell D. (Lead / Corresponding author); Samuel, Leslie M.; Murray, Graeme I.; MacDonald, Graham; O'Kelly, Terrence; Loudon, Malcolm; Binnie, Norman; Aly, Emad; McKinlay, Aileen; Wang, Weiguang; Gilbert, Fiona; Semple, Scot; Collie-Duguid, Elaina S. R. (Lead / Corresponding author).

    In: BMC Cancer, Vol. 9, 434, 11.12.2009.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling

    AU - Petty, Russell D.

    AU - Samuel, Leslie M.

    AU - Murray, Graeme I.

    AU - MacDonald, Graham

    AU - O'Kelly, Terrence

    AU - Loudon, Malcolm

    AU - Binnie, Norman

    AU - Aly, Emad

    AU - McKinlay, Aileen

    AU - Wang, Weiguang

    AU - Gilbert, Fiona

    AU - Semple, Scot

    AU - Collie-Duguid, Elaina S. R.

    PY - 2009/12/11

    Y1 - 2009/12/11

    N2 - BACKGROUND: 5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets.METHODS: Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified.RESULTS: APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent with APRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95%CI 1.48-26.32), p = 0.013].CONCLUSIONS: A combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.

    AB - BACKGROUND: 5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets.METHODS: Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified.RESULTS: APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent with APRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95%CI 1.48-26.32), p = 0.013].CONCLUSIONS: A combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.

    KW - Adenocarcinoma

    KW - Adult

    KW - Antineoplastic Agents

    KW - Colorectal Neoplasms

    KW - Drug Resistance, Neoplasm

    KW - Fluorouracil

    KW - Gene Expression

    KW - Gene Expression Profiling

    KW - Humans

    KW - Immunohistochemistry

    KW - Kaplan-Meier Estimate

    KW - Oligonucleotide Array Sequence Analysis

    KW - Tumor Markers, Biological

    KW - Tumor Necrosis Factor Ligand Superfamily Member 13

    U2 - 10.1186/1471-2407-9-434

    DO - 10.1186/1471-2407-9-434

    M3 - Article

    VL - 9

    JO - BMC Cancer

    JF - BMC Cancer

    SN - 1471-2407

    M1 - 434

    ER -