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Clinical and biological relevance of genomic heterogeneity in chronic lymphocytic leukemia.

Friedman DR, Lucas JE, Weinberg JB - PLoS ONE (2013)

Bottom Line: We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups.We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes.Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Duke University, Durham, North Carolina, USA. daphne.friedman@duke.edu

ABSTRACT

Background: Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients' leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL.

Methods: To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups.

Results: Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes.

Conclusions: Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways.

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A heatmap of oncogenic pathway signature predictions, with CLL samples grouped by genomically-defined subgroups on the x-axis, and signatures on the y-axis.Red denotes high signature prediction, and blue denotes low signature prediction, with prediction scores scaled by row. This demonstrates that subgroups have distinct patterns of oncogenic pathway activity, which confirm results obtained from GSEA analysis.
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pone-0057356-g004: A heatmap of oncogenic pathway signature predictions, with CLL samples grouped by genomically-defined subgroups on the x-axis, and signatures on the y-axis.Red denotes high signature prediction, and blue denotes low signature prediction, with prediction scores scaled by row. This demonstrates that subgroups have distinct patterns of oncogenic pathway activity, which confirm results obtained from GSEA analysis.

Mentions: The annotations revealed by GSEA were consistent with our analysis using gene expression signatures that measure oncogenic and cell signaling pathways. These signatures were developed from experimental perturbations of pathways and provide a quantitative estimate of the state of the cellular pathway in a given sample [36], [39]. As displayed in Figure 4, the predictions of pathway activity using these signatures revealed distinctions between the CLL subgroups. For example, subgroups one and two were found to have high TNFα/NF-κB pathway activity and subgroup four was found to have low activity, consistent with the analysis from GSEA. Further, subgroups two and six exhibited elevated interferon alpha and gamma pathway activity, again consistent with the annotations obtained by GSEA. These analyses underscore that subgroups defined by raw gene expression data have differences in underlying biology and pathway activation.


Clinical and biological relevance of genomic heterogeneity in chronic lymphocytic leukemia.

Friedman DR, Lucas JE, Weinberg JB - PLoS ONE (2013)

A heatmap of oncogenic pathway signature predictions, with CLL samples grouped by genomically-defined subgroups on the x-axis, and signatures on the y-axis.Red denotes high signature prediction, and blue denotes low signature prediction, with prediction scores scaled by row. This demonstrates that subgroups have distinct patterns of oncogenic pathway activity, which confirm results obtained from GSEA analysis.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585365&req=5

pone-0057356-g004: A heatmap of oncogenic pathway signature predictions, with CLL samples grouped by genomically-defined subgroups on the x-axis, and signatures on the y-axis.Red denotes high signature prediction, and blue denotes low signature prediction, with prediction scores scaled by row. This demonstrates that subgroups have distinct patterns of oncogenic pathway activity, which confirm results obtained from GSEA analysis.
Mentions: The annotations revealed by GSEA were consistent with our analysis using gene expression signatures that measure oncogenic and cell signaling pathways. These signatures were developed from experimental perturbations of pathways and provide a quantitative estimate of the state of the cellular pathway in a given sample [36], [39]. As displayed in Figure 4, the predictions of pathway activity using these signatures revealed distinctions between the CLL subgroups. For example, subgroups one and two were found to have high TNFα/NF-κB pathway activity and subgroup four was found to have low activity, consistent with the analysis from GSEA. Further, subgroups two and six exhibited elevated interferon alpha and gamma pathway activity, again consistent with the annotations obtained by GSEA. These analyses underscore that subgroups defined by raw gene expression data have differences in underlying biology and pathway activation.

Bottom Line: We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups.We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes.Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Duke University, Durham, North Carolina, USA. daphne.friedman@duke.edu

ABSTRACT

Background: Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients' leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL.

Methods: To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups.

Results: Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes.

Conclusions: Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways.

Show MeSH
Related in: MedlinePlus