Dataset Information

Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis.

ABSTRACT:

Background

B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.

Results

We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p.

Conclusions

Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential.

SUBMITTER: Georgiadis P

PROVIDER: S-EPMC5598006 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis.

Georgiadis Panagiotis P Liampa Irene I Hebels Dennie G DG Krauskopf Julian J Chatziioannou Aristotelis A Valavanis Ioannis I de Kok Theo M C M TMCM Kleinjans Jos C S JCS Bergdahl Ingvar A IA Melin Beatrice B Spaeth Florentin F Palli Domenico D Vermeulen R C H RCH Vlaanderen J J Chadeau-Hyam Marc M Vineis Paolo P Kyrtopoulos Soterios A SA

BMC genomics 20170913 1

<h4>Background</h4>B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potent ...[more]

PMID: 28903739

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Project description:BackgroundVibrotactile discrimination tasks have been used to examine decision making processes in the presence of perceptual uncertainty, induced by barely discernible frequency differences between paired stimuli or by the presence of embedded noise. One lesser known property of such tasks is that decisions made on a single trial may be biased by information from prior trials. An example is the time-order effect whereby the presentation order of paired stimuli may introduce differences in accuracy. Subjects perform better when the first stimulus lies between the second stimulus and the global mean of all stimuli on the judged dimension ("preferred" time-orders) compared to the alternative presentation order ("nonpreferred" time-orders). This has been conceptualised as a "drift" of the first stimulus representation towards the global mean of the stimulus-set (an internal standard). We describe the influence of prior information in relation to the more traditionally studied factors of interest in a classic discrimination task.MethodologySixty subjects performed a vibrotactile discrimination task with different levels of uncertainty parametrically induced by increasing task difficulty, aperiodic stimulus noise, and changing the task instructions whilst maintaining identical stimulus properties (the "context").Principal findingsThe time-order effect had a greater influence on task performance than two of the explicit factors-task difficulty and noise-but not context. The influence of prior information increased with the distance of the first stimulus from the global mean, suggesting that the "drift" velocity of the first stimulus towards the global mean representation was greater for these trials.Conclusions/significanceAwareness of the time-order effect and prior information in general is essential when studying perceptual decision making tasks. Implicit mechanisms may have a greater influence than the explicit factors under study. It also affords valuable insights into basic mechanisms of information accumulation, storage, sensory weighting, and processing in neural circuits.

Dataset Information

Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis.

Background

Results

Conclusions

Publications

Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis.

Similar Datasets

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