microRNAs have shown potential to be used as biomarkers for diagnosing and treating different types of cancers, though their application in doing so had yet to be determined.
Investigators identified new signatures of microRNAs (miRNA) of relevance in diffuse large B-cell lymphoma (DLBCL) that have the potential to improve diagnosis, subtype characterization, and treatment response through small RNA sequencing, according to the results of a study published in Scientific Reports.
Although 75%-80% of patients with DLBCL undergo complete remission after treatment with standard chemotherapy regimens, the remaining patients end up being refractory to first-line chemotherapy, with 30%-40% relapsing after complete remission. These observations prompted investigators to search for new biomarkers for better management of DLBCL.
miRNAs have shown potential as post-transcriptional regulators of gene expression and biological functions to be used as diagnostic, classification, and prognostic predictors in cancer. Investigators sought to determine a set of miRNAs with the best utility in DLBCL using small RNA sequencing.
Researchers identified 1584 miRNAs through a sequencing analysis. Further examination showed that 146 miRNAs exhibited statistically significant differences in expression between samples of DLBCL patients at diagnosis and control samples. Of these 146 miRNAs, 122 showed increased abundance in DLBCL.
In examining miRNAs associated with treatment response to DLBCL, 11 miRNA were differentially expressed between samples at diagnosis from patients with long-term complete remission (n = 50) and refractory patients (n = 12). From these, 10 miRNAs were upregulated in patients with complete remission, whereas 1 miRNA was downregulated in the same group, the study investigators found.
Moving to an analysis of miRNAs as prognostic biomarkers in DLBCL and their impact on survival, the investigators compared miRNA expression at diagnosis of 50 patients with long-term remission and 16 patients who relapsed within 10 years after diagnosis. Results of the comparison indicated 7 miRNAs were significantly upregulated in patients with long-term remission, whereas 3 miRNAs were significantly upregulated in patients who had relapsed.
Researchers then generated patient survival curves to represent 5-year progression-free survival (PFS) and overall survival (OS), dividing patients into high-expression and low-expression groups. The test revealed that high expression of miR-370-3p was associated with better 5-year PFS (OS p-value = 0.17, PFS p-value = 0.025).
Notably, all the miRNAs that were previously proposed as a consistent signature of deregulation in DLBCL in a systematic review by the study authors were identified in the current study with a similar expression pattern. Furthermore, they identified previously unknown miRNAs that were highly deregulated in DLBCL.
Additionally, the study investigators identified a predictive miRNA signature for therapy response. This included the upregulation of 10 miRNAs in association with good response and upregulation of miR-192-5p, which was associated with chemoresistance to R-CHOP DLBCL, the researchers found.
The researchers also determined that these miRNAs could be used as novel therapeutic targets for personalized miRNA-based therapy in the future, though they cautioned that further studies in that area of research were needed before those therapies could be translated at the clinic level.
Significantly, regarding the upregulated genes in DLBCL that could be a consequence of miRNA downregulation, evidence revealed that elevated expression of anti-apoptotic members, such as BCL2, is one of the major contributing factors to B cell lymphomagenesis, the investigators discussed. They found that the gene could be regulated negatively by miR-135a-5p, miR-234-5p, miR-139-5p, miR-451a, and miR-497-5p.
Some study limitations addressed by the researchers include patients being diagnosed in 3 different hospitals with different follow-up routines and potentially inconsistent results due to use of the Han’s immunohistochemical algorithm to classify patients into subtypes.
“Prospective studies are warranted to further validate our findings and explore new therapeutic options based on the miRNA profile of each patient,” the study authors concluded.
Larrabeiti-Etxebarria A, Bilbao-Aldaiturriaga N, Arzuaga-Mendez J, et al. microRNA sequencing for biomarker detection in the diagnosis, classification and prognosis of diffuse large B cell lymphoma. Sci Rep. 2023;13(1):12159. doi:10.1038/s41598-023-39271-7.