Diagnostic and prognostic utility of a DNA hypermethylated gene signature in prostate cancer

Liang Kee Goh, Natalia Liem, Aadhitthya Vijayaraghavan, Gengbo Chen, Pei Li Lim, Kae Jack Tay, Michelle Chang, John Soon Wah Low, Adita Joshi, Hong Hong Huang, Emarene Kalaw, Puay Hoon Tan, Wen Son Hsieh, Wei Peng Yong, Joshi Alumkal, Hong Gee Sim

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    We aimed to identify a prostate cancer DNA hypermethylation microarray signature (denoted as PHYMA) that differentiates prostate cancer from benign prostate hyperplasia (BPH), high from low-grade and lethal from non-lethal cancers. This is a non-randomized retrospective study in 111 local Asian men (87 prostate cancers and 24 BPH) treated from 1995 to 2009 in our institution. Archival prostate epithelia were laser-capture microdissected and genomic DNA extracted and bisulfite-converted. Samples were profiled using Illumina GoldenGate Methylation microarray, with raw data processed by GenomeStudio. A classification model was generated using support vector machine, consisting of a 55-probe DNA methylation signature of 46 genes. The model was independently validated on an internal testing dataset which yielded cancer detection sensitivity and specificity of 95.3% and 100% respectively, with overall accuracy of 96.4%. Second validation on another independent western cohort yielded 89.8% sensitivity and 66.7% specificity, with overall accuracy of 88.7%. A PHYMA score was developed for each sample based on the state of methylation in the PHYMA signature. Increasing PHYMA score was significantly associated with higher Gleason score and Gleason primary grade. Men with higher PHYMA scores have poorer survival on univariate (p = 0.0038, HR = 3.89) and multivariate analyses when controlled for (i) clinical stage (p = 0.055, HR = 2.57), and (ii) clinical stage and Gleason score (p = 0.043, HR = 2.61). We further performed bisulfite genomic sequencing on 2 relatively unknown genes to demonstrate robustness of the assay results. PHYMA is thus a signature with high sensitivity and specificity for discriminating tumors from BPH, and has a potential role in early detection and in predicting survival.

    Original languageEnglish (US)
    Article numbere91666
    JournalPLoS One
    Volume9
    Issue number3
    DOIs
    StatePublished - Mar 13 2014

    Fingerprint

    Methylation
    prostatic neoplasms
    Microarrays
    hyperplasia
    bisulfites
    Prostatic Neoplasms
    Genes
    Hyperplasia
    Prostate
    methylation
    neoplasms
    Neoplasm Grading
    DNA
    Sensitivity and Specificity
    Support vector machines
    genomics
    Tumors
    Assays
    genes
    DNA methylation

    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

    Cite this

    Goh, L. K., Liem, N., Vijayaraghavan, A., Chen, G., Lim, P. L., Tay, K. J., ... Sim, H. G. (2014). Diagnostic and prognostic utility of a DNA hypermethylated gene signature in prostate cancer. PLoS One, 9(3), [e91666]. https://doi.org/10.1371/journal.pone.0091666

    Diagnostic and prognostic utility of a DNA hypermethylated gene signature in prostate cancer. / Goh, Liang Kee; Liem, Natalia; Vijayaraghavan, Aadhitthya; Chen, Gengbo; Lim, Pei Li; Tay, Kae Jack; Chang, Michelle; Low, John Soon Wah; Joshi, Adita; Huang, Hong Hong; Kalaw, Emarene; Tan, Puay Hoon; Hsieh, Wen Son; Yong, Wei Peng; Alumkal, Joshi; Sim, Hong Gee.

    In: PLoS One, Vol. 9, No. 3, e91666, 13.03.2014.

    Research output: Contribution to journalArticle

    Goh, LK, Liem, N, Vijayaraghavan, A, Chen, G, Lim, PL, Tay, KJ, Chang, M, Low, JSW, Joshi, A, Huang, HH, Kalaw, E, Tan, PH, Hsieh, WS, Yong, WP, Alumkal, J & Sim, HG 2014, 'Diagnostic and prognostic utility of a DNA hypermethylated gene signature in prostate cancer', PLoS One, vol. 9, no. 3, e91666. https://doi.org/10.1371/journal.pone.0091666
    Goh, Liang Kee ; Liem, Natalia ; Vijayaraghavan, Aadhitthya ; Chen, Gengbo ; Lim, Pei Li ; Tay, Kae Jack ; Chang, Michelle ; Low, John Soon Wah ; Joshi, Adita ; Huang, Hong Hong ; Kalaw, Emarene ; Tan, Puay Hoon ; Hsieh, Wen Son ; Yong, Wei Peng ; Alumkal, Joshi ; Sim, Hong Gee. / Diagnostic and prognostic utility of a DNA hypermethylated gene signature in prostate cancer. In: PLoS One. 2014 ; Vol. 9, No. 3.
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    abstract = "We aimed to identify a prostate cancer DNA hypermethylation microarray signature (denoted as PHYMA) that differentiates prostate cancer from benign prostate hyperplasia (BPH), high from low-grade and lethal from non-lethal cancers. This is a non-randomized retrospective study in 111 local Asian men (87 prostate cancers and 24 BPH) treated from 1995 to 2009 in our institution. Archival prostate epithelia were laser-capture microdissected and genomic DNA extracted and bisulfite-converted. Samples were profiled using Illumina GoldenGate Methylation microarray, with raw data processed by GenomeStudio. A classification model was generated using support vector machine, consisting of a 55-probe DNA methylation signature of 46 genes. The model was independently validated on an internal testing dataset which yielded cancer detection sensitivity and specificity of 95.3{\%} and 100{\%} respectively, with overall accuracy of 96.4{\%}. Second validation on another independent western cohort yielded 89.8{\%} sensitivity and 66.7{\%} specificity, with overall accuracy of 88.7{\%}. A PHYMA score was developed for each sample based on the state of methylation in the PHYMA signature. Increasing PHYMA score was significantly associated with higher Gleason score and Gleason primary grade. Men with higher PHYMA scores have poorer survival on univariate (p = 0.0038, HR = 3.89) and multivariate analyses when controlled for (i) clinical stage (p = 0.055, HR = 2.57), and (ii) clinical stage and Gleason score (p = 0.043, HR = 2.61). We further performed bisulfite genomic sequencing on 2 relatively unknown genes to demonstrate robustness of the assay results. PHYMA is thus a signature with high sensitivity and specificity for discriminating tumors from BPH, and has a potential role in early detection and in predicting survival.",
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    AU - Vijayaraghavan, Aadhitthya

    AU - Chen, Gengbo

    AU - Lim, Pei Li

    AU - Tay, Kae Jack

    AU - Chang, Michelle

    AU - Low, John Soon Wah

    AU - Joshi, Adita

    AU - Huang, Hong Hong

    AU - Kalaw, Emarene

    AU - Tan, Puay Hoon

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