Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis

Abstract

Background: B-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms.

Methods: We investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts.

Results: Our analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection.

Conclusions: This is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

Keywords: chronic lymphocytic leukemia; epidemiology; lymphoma; mRNA analyses; prospective cohort.

Figure 1.

Physical repartition of the genes whose expression is measured by the 745 CLL-specific candidates. The per-chromosome proportion of significant probes (Figure 2A) is calculated from the 739 probes whose chromosome is annotated over the total number of probes assayed per chromosome. Figure 2B summarizes the expression levels in cases and controls for the probes relating to each of the 24 chromosomes (total 739 in which the chromosome is annotated). Figure 2C displays for each probe (labeled and colored accordingly to the chromosome they belong to) the P-value measuring the association with the disease status as a function of their effect size estimate (fold-change).

Figure 2.

Quantitative assessment of the predictive abilities of the CLL candidate probes. Combinations of probes were selected based on a stepwise procedure including one probe at a time in a logistic model. At each step of the iterative procedure, an additional probe was added to the model such that it maximized the gain in AUC for the resulting ROC curve compared with the probe combination retained at the previous step. The plot presents the density estimate of the AUC at different steps of the algorithm (models containing 1, 5, 10, 20, and 40 probes).