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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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Related in: MedlinePlus

Kaplan-Meier analysis of time from diagnosis to treatment in sixty-eight CLL patient samples, grouped by genomically-defined subgroup.A) A significant difference in overall survival was observed between CLL subgroups (p  = 0.004). B) CLL patients in “Interferon Pathway” subgroups had inferior overall survival compared to CLL patients in the “Receptor Signaling” subgroup (p  = 0.03). Significance was assessed using the log-rank test.
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pone-0057356-g005: Kaplan-Meier analysis of time from diagnosis to treatment in sixty-eight CLL patient samples, grouped by genomically-defined subgroup.A) A significant difference in overall survival was observed between CLL subgroups (p  = 0.004). B) CLL patients in “Interferon Pathway” subgroups had inferior overall survival compared to CLL patients in the “Receptor Signaling” subgroup (p  = 0.03). Significance was assessed using the log-rank test.

Mentions: To assess the relationship between the CLL subgroups and clinical outcomes further, we evaluated overall survival in 68 CLL samples from our institution evaluated previously (GSE10138) [12]. When we updated our clinical outcomes data, we found that patients grouped based on the genomically-defined subgroups had significantly different overall survival (Figure 5A, p  = 0.004, log-rank test). Of the molecular prognostic markers, CD38 and FISH results were significantly associated with overall survival in this cohort (p  = 0.047 and 0.01 respectively, log-rank test), whereas IgVH and ZAP70 status were not. We then assessed the extent to which subgroups with particular gene and pathway annotations had disparate clinical outcomes. As seen in Figure 5B, we found that CLL patients that fell into subgroups with interferon pathway annotations (subgroups two and six) had significantly worse outcomes than patients with samples that fell into the subgroup with B-cell receptor signaling annotations (subgroup five). These pathway annotations were evaluated because B-cell receptor signaling is a known important cellular pathway in CLL, while the interferon pathway and inflammation has not been traditionally studied with regards to CLL biology.


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

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

Kaplan-Meier analysis of time from diagnosis to treatment in sixty-eight CLL patient samples, grouped by genomically-defined subgroup.A) A significant difference in overall survival was observed between CLL subgroups (p  = 0.004). B) CLL patients in “Interferon Pathway” subgroups had inferior overall survival compared to CLL patients in the “Receptor Signaling” subgroup (p  = 0.03). Significance was assessed using the log-rank test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057356-g005: Kaplan-Meier analysis of time from diagnosis to treatment in sixty-eight CLL patient samples, grouped by genomically-defined subgroup.A) A significant difference in overall survival was observed between CLL subgroups (p  = 0.004). B) CLL patients in “Interferon Pathway” subgroups had inferior overall survival compared to CLL patients in the “Receptor Signaling” subgroup (p  = 0.03). Significance was assessed using the log-rank test.
Mentions: To assess the relationship between the CLL subgroups and clinical outcomes further, we evaluated overall survival in 68 CLL samples from our institution evaluated previously (GSE10138) [12]. When we updated our clinical outcomes data, we found that patients grouped based on the genomically-defined subgroups had significantly different overall survival (Figure 5A, p  = 0.004, log-rank test). Of the molecular prognostic markers, CD38 and FISH results were significantly associated with overall survival in this cohort (p  = 0.047 and 0.01 respectively, log-rank test), whereas IgVH and ZAP70 status were not. We then assessed the extent to which subgroups with particular gene and pathway annotations had disparate clinical outcomes. As seen in Figure 5B, we found that CLL patients that fell into subgroups with interferon pathway annotations (subgroups two and six) had significantly worse outcomes than patients with samples that fell into the subgroup with B-cell receptor signaling annotations (subgroup five). These pathway annotations were evaluated because B-cell receptor signaling is a known important cellular pathway in CLL, while the interferon pathway and inflammation has not been traditionally studied with regards to CLL biology.

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