Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer

Russell D. Petty (Lead / Corresponding author), Keith M. Kerr, Graeme I. Murray, Marianne C. Nicolson, Patrick H. Rooney, Donald Bissett, Elaina S. R. Collie-Duguid (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    42 Citations (Scopus)

    Abstract

    PURPOSE: Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC).

    METHODS: Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry.

    RESULTS: Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72).

    CONCLUSION: This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.

    Original languageEnglish
    Pages (from-to)1729-1744
    Number of pages16
    JournalJournal of Clinical Oncology
    Volume24
    Issue number11
    DOIs
    Publication statusPublished - 5 Apr 2006

    Fingerprint

    Protease Inhibitors
    Transcriptome
    Non-Small Cell Lung Carcinoma
    Platinum
    Drug Therapy
    Cystatin C
    Neoplasms
    Immunohistochemistry
    Cathepsin B
    Gene Expression Profiling
    Computational Biology
    Cluster Analysis
    Squamous Cell Carcinoma
    Adenocarcinoma
    Peptide Hydrolases
    Lymph Nodes
    Odds Ratio
    Gene Expression
    Lung
    Messenger RNA

    Keywords

    • Aged
    • Antineoplastic Agents
    • Carcinoma, Non-Small-Cell Lung
    • Cystatin C
    • Cystatins
    • Female
    • Gene Expression Profiling
    • Humans
    • Lung Neoplasms
    • Male
    • Middle Aged
    • Prognosis
    • Serine Proteinase Inhibitors
    • Serpins

    Cite this

    Petty, Russell D. ; Kerr, Keith M. ; Murray, Graeme I. ; Nicolson, Marianne C. ; Rooney, Patrick H. ; Bissett, Donald ; Collie-Duguid, Elaina S. R. / Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 11. pp. 1729-1744.
    @article{08af8eef61b3404ea33a8896898fb572,
    title = "Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer",
    abstract = "PURPOSE: Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC).METHODS: Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-na{\"i}ve NSCLC patients using immunohistochemistry.RESULTS: Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95{\%} CI, 2.0 to 162.4; P = .01), with an accuracy of 72{\%}. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95{\%} CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95{\%} CI, 1.03 to 4.72).CONCLUSION: This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.",
    keywords = "Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cystatin C, Cystatins, Female, Gene Expression Profiling, Humans, Lung Neoplasms, Male, Middle Aged, Prognosis, Serine Proteinase Inhibitors, Serpins",
    author = "Petty, {Russell D.} and Kerr, {Keith M.} and Murray, {Graeme I.} and Nicolson, {Marianne C.} and Rooney, {Patrick H.} and Donald Bissett and Collie-Duguid, {Elaina S. R.}",
    year = "2006",
    month = "4",
    day = "5",
    doi = "10.1200/JCO.2005.03.3399",
    language = "English",
    volume = "24",
    pages = "1729--1744",
    journal = "Journal of Clinical Oncology",
    issn = "0732-183X",
    publisher = "American Society of Clinical Oncology",
    number = "11",

    }

    Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer. / Petty, Russell D. (Lead / Corresponding author); Kerr, Keith M.; Murray, Graeme I.; Nicolson, Marianne C.; Rooney, Patrick H.; Bissett, Donald; Collie-Duguid, Elaina S. R. (Lead / Corresponding author).

    In: Journal of Clinical Oncology, Vol. 24, No. 11, 05.04.2006, p. 1729-1744.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer

    AU - Petty, Russell D.

    AU - Kerr, Keith M.

    AU - Murray, Graeme I.

    AU - Nicolson, Marianne C.

    AU - Rooney, Patrick H.

    AU - Bissett, Donald

    AU - Collie-Duguid, Elaina S. R.

    PY - 2006/4/5

    Y1 - 2006/4/5

    N2 - PURPOSE: Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC).METHODS: Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry.RESULTS: Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72).CONCLUSION: This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.

    AB - PURPOSE: Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC).METHODS: Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry.RESULTS: Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72).CONCLUSION: This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.

    KW - Aged

    KW - Antineoplastic Agents

    KW - Carcinoma, Non-Small-Cell Lung

    KW - Cystatin C

    KW - Cystatins

    KW - Female

    KW - Gene Expression Profiling

    KW - Humans

    KW - Lung Neoplasms

    KW - Male

    KW - Middle Aged

    KW - Prognosis

    KW - Serine Proteinase Inhibitors

    KW - Serpins

    U2 - 10.1200/JCO.2005.03.3399

    DO - 10.1200/JCO.2005.03.3399

    M3 - Article

    VL - 24

    SP - 1729

    EP - 1744

    JO - Journal of Clinical Oncology

    JF - Journal of Clinical Oncology

    SN - 0732-183X

    IS - 11

    ER -