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Curation-free biomodules mechanisms in prostate cancer predict recurrent disease.

ABSTRACT: Gene expression-based prostate cancer gene signatures of poor prognosis are hampered by lack of gene feature reproducibility and a lack of understandability of their function. Molecular pathway-level mechanisms are intrinsically more stable and more robust than an individual gene. The Functional Analysis of Individual Microarray Expression (FAIME) we developed allows distinctive sample-level pathway measurements with utility for correlation with continuous phenotypes (e.g. survival). Further, we and others have previously demonstrated that pathway-level classifiers can be as accurate as gene-level classifiers using curated genesets that may implicitly comprise ascertainment biases (e.g. KEGG, GO). Here, we hypothesized that transformation of individual prostate cancer patient gene expression to pathway-level mechanisms derived from automated high throughput analyses of genomic datasets may also permit personalized pathway analysis and improve prognosis of recurrent disease.Via FAIME, three independent prostate gene expression arrays with both normal and tumor samples were transformed into two distinct types of molecular pathway mechanisms: (i) the curated Gene Ontology (GO) and (ii) dynamic expression activity networks of cancer (Cancer Modules). FAIME-derived mechanisms for tumorigenesis were then identified and compared. Curated GO and computationally generated "Cancer Module" mechanisms overlap significantly and are enriched for known oncogenic deregulations and highlight potential areas of investigation. We further show in two independent datasets that these pathway-level tumorigenesis mechanisms can identify men who are more likely to develop recurrent prostate cancer (log-rank_p = 0.019).Curation-free biomodules classification derived from congruent gene expression activation breaks from the paradigm of recapitulating the known curated pathway mechanism universe.

SUBMITTER: Chen JL

PROVIDER: S-EPMC3654873 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Curation-free biomodules mechanisms in prostate cancer predict recurrent disease.

Chen James L JL Hsu Alexander A Yang Xinan X Li Jianrong J Lee Younghee Y Parinandi Gurunadh G Li Haiquan H Lussier Yves A YA

BMC medical genomics 20130507

<h4>Motivation</h4>Gene expression-based prostate cancer gene signatures of poor prognosis are hampered by lack of gene feature reproducibility and a lack of understandability of their function. Molecular pathway-level mechanisms are intrinsically more stable and more robust than an individual gene. The Functional Analysis of Individual Microarray Expression (FAIME) we developed allows distinctive sample-level pathway measurements with utility for correlation with continuous phenotypes (e.g. sur ...[more]

PMID: 23819917

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Project description:IntroductionTissue cryoablation is a potential curative option for solid malignancies, including radiation recurrent prostate cancer (RRPC). Case series of salvage cryotherapy (SCT) in RRPC have reported promising disease free survival (DFS) outcomes and acceptable toxicity profile. While many men receive SCT, no predictive factors for treatment induced side effects are known. The aim of this study is to validate the oncologic outcome of SCT in a large multi-centre patient cohort and to identify potential parameters associated with an increased risk of micturition symptoms.Patients and methodsIn this retrospective analysis, we studied 283 consecutive patients with RRPC treated by SCT in three independent U.K. centres (between 2001 and 2011). Two freeze-thaw cycles of transperineal cryotherapy were performed under transrectal ultrasound guidance by a single surgeon in each of the 3 sites. We analysed clinico-pathological factors against tumour response. Functional outcomes were assessed by continence status and IPSS questionnaire. Predictive factors for SCT-induced micturition symptoms were analysed in a sub-group (n=42) of consecutive cases.ResultsWe found that nadir post-SCT PSA levels strongly associated with DFS. The DFS rates at 12- and 36-month were 84% and 67% for the ? 1 ng/ml group and 56% and 14% for the >1 ng/ml group, respectively (p<0.001). Correlative analysis revealed highly significant association between patients' post-SCT micturition status with prostate gland and iceball lengths following SCT. Finally, in a reduction model, both gland length and maximal length of iceball were highly associated with patients' IPSS outcome (p<0.001).ConclusionWe report the largest European patient cohort treated with SCT for RRPC. Oncologic outcome guided by nadir PSA of <1 ng/ml is consistent with earlier single-centre series. For the first time, we identified physical parameters to predict micturition symptoms following SCT. Our data will directly assist on-going and future trial design in cryotherapy in prostate cancer.

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Curation-free biomodules mechanisms in prostate cancer predict recurrent disease.

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Curation-free biomodules mechanisms in prostate cancer predict recurrent disease.

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