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Peeling off the hidden genetic heterogeneities of cancers based on disease-relevant functional modules.

ABSTRACT: Discovering molecular heterogeneities in phenotypically defined disease is of critical importance both for understanding pathogenic mechanisms of complex diseases and for finding efficient treatments. Recently, it has been recognized that cellular phenotypes are determined by the concerted actions of many functionally related genes in modular fashions. The underlying modular mechanisms should help the understanding of hidden genetic heterogeneities of complex diseases. We defined a putative disease module to be the functional gene groups in terms of both biological process and cellular localization, which are significantly enriched with genes highly variably expressed across the disease samples. As a validation, we used two large cancer datasets to evaluate the ability of the modules for correctly partitioning samples. Then, we sought the subtypes of complex diffuse large B-cell lymphoma (DLBCL) using a public dataset. Finally, the clinical significance of the identified subtypes was verified by survival analysis. In two validation datasets, we achieved highly accurate partitions that best fit the clinical cancer phenotypes. Then, for the notoriously heterogeneous DLBCL, we demonstrated that two partitioned subtypes using an identified module ("cellular response to stress") had very different 5-year overall rates (65% vs. 14%) and were highly significantly (P < 0.007) correlated with the clinical survival rate. Finally, we built a multivariate Cox proportional-hazard prediction model that included 4 genes as risk predictors for survival over DLBCL. The proposed modular approach is a promising computational strategy for peeling off genetic heterogeneities and understanding the modular mechanisms of human diseases such as cancers.

SUBMITTER: Xu JZ

PROVIDER: S-EPMC1514552 | biostudies-literature | 2006 Jan-Mar

REPOSITORIES: biostudies-literature

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Peeling off the hidden genetic heterogeneities of cancers based on disease-relevant functional modules.

Xu Jian-Zhen JZ Guo Zheng Z Zhang Min M Li Xia X Li Yong-Jin YJ Rao Shao-Qi SQ

Molecular medicine (Cambridge, Mass.) 20060101 1-3

Discovering molecular heterogeneities in phenotypically defined disease is of critical importance both for understanding pathogenic mechanisms of complex diseases and for finding efficient treatments. Recently, it has been recognized that cellular phenotypes are determined by the concerted actions of many functionally related genes in modular fashions. The underlying modular mechanisms should help the understanding of hidden genetic heterogeneities of complex diseases. We defined a putative dise ...[more]

PMID: 16838067

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Project description:BackgroundIt becomes increasingly clear that our current taxonomy of clinical phenotypes is mixed with molecular heterogeneity. Of vital importance for refined clinical practice and improved intervention strategies is to define the hidden molecular distinct diseases using modern large-scale genomic approaches. Microarray omics technology has provided a powerful way to dissect hidden genetic heterogeneity of complex diseases. The aim of this study was thus to develop a bioinformatics approach to seek the transcriptional features leading to the hidden subtyping of a complex clinical phenotype. The basic strategy of the proposed method was to iteratively partition in two ways sample and feature space with super-paramagnetic clustering technique and to seek for hard and robust gene clusters that lead to a natural partition of disease samples and that have the highest functionally conceptual consensus evaluated with Gene Ontology.ResultsWe applied the proposed method to two publicly available microarray datasets of diffuse large B-cell lymphoma (DLBCL), a notoriously heterogeneous phenotype. A feature subset of 30 genes (38 probes) derived from analysis of the first dataset consisting of 4026 genes and 42 DLBCL samples identified three categories of patients with very different five-year overall survival rates (70.59%, 44.44% and 14.29% respectively; p = 0.0017). Analysis of the second dataset consisting of 7129 genes and 58 DLBCL samples revealed a feature subset of 13 genes (16 probes) that not only replicated the findings of the important DLBCL genes (e.g. JAW1 and BCL7A), but also identified three clinically similar subtypes (with 5-year overall survival rates of 63.13%, 34.92% and 15.38% respectively; p = 0.0009) to those identified in the first dataset. Finally, we built a multivariate Cox proportional-hazards prediction model for each feature subset and defined JAW1 as one of the most significant predictor (p = 0.005 and 0.014; hazard ratios = 0.02 and 0.03, respectively for two datasets) for both DLBCL cohorts under study.ConclusionOur results showed that the proposed algorithm is a promising computational strategy for peeling off the hidden genetic heterogeneity based on transcriptionally profiling disease samples, which may lead to an improved diagnosis and treatment of cancers.

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Peeling off the hidden genetic heterogeneities of cancers based on disease-relevant functional modules.

Publications

Peeling off the hidden genetic heterogeneities of cancers based on disease-relevant functional modules.

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