The value of circulating microRNAs for early diagnosis of B-cell lymphoma: A case-control study on historical samples

Abstract

MicroRNAs are small regulatory RNAs that are deregulated in a wide variety of human cancers, including different types of B-cell lymphoma. Nevertheless, the feasibility of circulating microRNA for early diagnosis of B-cell lymphoma has not been established. To address the possibility of detecting specific circulating microRNAs years before a B-cell lymphoma is diagnosed, we studied the plasma expression of microRNA first in pre-treatment samples from patients with diffuse large B-cell lymphoma and subsequently in repository samples from blood donors who later developed B-cell lymphomas. In addition, we studied the microRNA expression in the diagnostic lymphoma biopsy. The most strongly induced (miR-326) and suppressed (miR-375) plasma microRNA at diagnosis, when compared with healthy blood donors, were also substantially up-or down-regulated in plasma repository samples taken from several months to up to two years before the blood donors were diagnosed with B-cell lymphoma. Importantly, at these time points the donors had no signs of disease and felt healthy enough to donate blood. In conclusion, this first study of plasma microRNA profiles from apparently healthy individuals, taken several years before B-cell lymphoma diagnosis, suggests that plasma microRNA profiles may be predictive of lymphoma development. B cell lymphomas are the most common hematological cancer in adults with reported annual incidence rates of around 21/100,000 persons in DK 1. A wide variety of B-cell lymphoma subtypes are recognized by the WHO classification, the most common of which are diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) 2. Despite significant improvements in outcome, DLBCL as such still carry considerable mortality with an overall three year survival of around 75% 3. Accordingly, there is a need for biomarkers that are readily applicable in the clinic to facilitate early detection and treatment of patients. Circulating microRNAs may be of potential interest in this regard. MicroRNAs are small RNA strands, consisting of 18 to 23 nucleotides, that regulate the activity of messenger RNA (mRNA) 4. They are detectable-and have been shown to be quite stable in plasma samples despite the presence of RNases 5,6. Therefore, microRNAs have attracted considerable attention in recent years, and multiple studies have repeatedly demonstrated that they are dysregulated in virtually all malignancies 7. In particular, aberrant serum levels of different microRNAs have been reported in patients with various types of lymphoma 8-13 .

Advances in Lymphoma Molecular Diagnostics

“…One group of researchers correlated serum levels of miR-224, miR-455-3p, miR-1236, miR-33a and miR-520d-3p with responses to classic chemotherapy [ 133 ]. More recently, one study analyzed the plasma repository samples of 16 blood donors taken months or years before the diagnosis of DLBCL [ 134 ]. They observed upregulated microRNAs at the time of diagnosis, namely miR-328, miR-21-5p, miR-326 and miR-199a-5p.…”

“…They observed upregulated microRNAs at the time of diagnosis, namely miR-328, miR-21-5p, miR-326 and miR-199a-5p. Interestingly miR-326 and miR-199a-5p were also upregulated in the last sample before diagnosis, indicating that these miRNAs were already upregulated in the absence of symptoms or diagnosis [ 134 ]. Similarly, miR-375 was found to be most down-regulated in DLBCL patients.…”

Circulating RNA biomarkers in diffuse large B-cell lymphoma: a systematic review

“…MiR-145 and miR-375 were lower in two studies and are considered tumor suppressors in different cancer types. MiR-145 targets among others the oncogenes MYC and protein C-ets-1 (ETS1), and miR-375 targets the astrocyte elevated gene 1 (AEG-1), yes-associated protein 1 (YAP1), insulin like growth factor 1 (IGF1R) and pyruvate dehydrogenase kinase isoenzyme 1 (PDK1) [58,63,[66][67][68]. MiR-15a was higher in three different studies [55,64,69].…”

“…MiR-155 is generally known as an oncomiR in many different tumors, targeting genes that play a central role in lymphomagenesis, such as suppressor of cytokine signaling (SOCS), phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1) and src homology 2-domain-containing inositol 5′-phosphatase 1 (SHIP1) [ specimens [77]. Interestingly, dysregulation of cell-free miRNAs may precede the diagnosis up to 2 years, highlighting their potential as early biomarkers, before the onset of clinical symptoms [66]. For DLBCL subclassification, no miRNA was found to be significantly dysregulated in at least two different studies.…”

Competitive Endogenous RNA Network Involving miRNA and lncRNA in Non-Hodgkin Lymphoma: Current Advances and Clinical Perspectives

“…Subsequently, they validated the identified miRNA signature in a confirmatory cohort comprising samples from blood donors, who later developed different types of B-cell lymphoma to test pre-diagnostic plasma samples for early diagnosis. In the end, they verified that both miR-326 and miR199a-5p were upregulated months to years before diagnosis, which showed that changes in plasma miRNAs may precede the development of symptoms of NHL [ 126 ].…”