Plasma microRNA are disease response biomarkers in classical Hodgkin lymphoma.
OBJECTIVE
Although microRNAs (miRNA) show potential as diagnostic biomarkers in cancer, their role as circulating cell-free disease response biomarkers remains unknown. Candidate circulating miRNA biomarkers for classical Hodgkin lymphoma (cHL) might arise from Hodgkin-Reed-Sternberg (HRS) cells and/or nonmalignant tumor-infiltrating cells. HRS cells are sparse within the diseased node, embedded within a benign microenvironment, the composition of which is distinct from that seen in healthy lymph nodes.


METHODS
Microarray profiling of more than 1,000 human miRNAs in 14 cHL primary tissues and eight healthy lymph nodes revealed a number of new disease node-associated miRNAs, including miR-494 and miR-1973. Using quantitative real-time PCR (qRT-PCR), we tested the utility of these, as well as previously identified disease node-associated plasma miRNAs (including miR-21 and miR-155), as disease response biomarkers in a prospective cohort of 42 patients with cHL. Blood samples were taken in conjunction with radiologic imaging at fixed time points before, during, and after therapy. Absolute quantification was used so as to facilitate implementation in diagnostic laboratories.


RESULTS
Levels of miR-494, miR-1973, and miR-21 were higher in patients than control (n = 20) plasma (P = 0.004, P = 0.007, and P < 0.0001, respectively). MiR-494 and miR-21 associated with Hasenclever scores ≥3. Strikingly, all three miRNAs returned to normal at remission (P = 0.0006, P = 0.0002, and P < 0.0001 respectively). However, only miR-494 and miR-1973 reflected interim therapy response with reduction being more pronounced in patients achieving complete versus partial responses (P = 0.043 and P = 0.0012, respectively).


CONCLUSIONS
Our results demonstrate that in patients with cHL, circulating cell-free miRNAs can reflect disease response once therapy has commenced.
Authors' Affiliations: Clinical Immunohaematology Laboratory, QIMR Berghofer Medical Research Institute; Centre for Experimental Haematology, University of Queensland School of Medicine, Translational Research Institute; Department of Haematology, Princess Alexandra Hospital, Brisbane, Queensland; and Griffith University, Gold Coast, Australia.
Kimberley
K
Jones
Jamie P
JP
Nourse
Colm
C
Keane
Atul
A
Bhatnagar
Maher K
MK
Gandhi
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D006689:Hodgkin Disease / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011446:Prospective Studies; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D016896:Treatment Outcome; D055815:Young Adult
D014408:Biomarkers, Tumor; D035683:MicroRNAs