Identification of a Novel Prognostic microRNA Signature in Mantle Cell Lymphoma
Rashmi S Goswami, Eshetu G Atenafu, Levi Waldron, Yali Xuan, Wei Xu, Patricia P Reis, John Kuruvilla, David J Good, Denis J Bailey, Raymond Lai, Alanna Church, Wilson S Lam, David P LeBrun, Laurie H Sehn, Pedro Farinha, Randy D Gascoyne, Michael R Crump, Igor Jurisica, Suzanne Kamel-Reid. University Health Network, Toronto, Canada; Harvard School of Public Health, Boston, MA; Universidade Estadual Paulista Júlio de Mesquita Filho, Botucatu, SP, Brazil; Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Cross Cancer Institute, Edmonton, AB, Canada; Queen's University, Kingston, ON, Canada; British Columbia Cancer Agency, Vancouver, BC, Canada; Ontario Cancer Institute, Toronto, ON, Canada
Background: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) that is sensitive to combination chemotherapy, with short remission durations. The clinical course is variable; some patients succumb quickly, while others survive >10 years. MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression by inhibiting mRNA translation. miRs are useful in the prognostic assessment of tumors, but work to date has only identified 2 miRs involved in MCL prognosis. We hypothesized that a miR signature obtained by comparing miR expression profiles of aggressive NHL with indolent NHL, when applied to a set of MCL cases, may aid in MCL prognosis.
Design: miR expression profiles of 20 aggressive and 19 indolent NHL (excluding MCL) were compared to one another to generate a signature based on differential miR expression between the two groups. The most significantly deregulated miRs were then validated on an independent set of 19 aggressive and 25 indolent NHL (excluding MCL). Expression of validated miRs was further tested on a set of 238 MCL samples acquired from 4 separate institutions. Principal component analysis of the miR signature was used to devise a scoring system dividing the MCL cases into separate prognostic groups. This was compared to Ki67 scores to determine prognostic utility of the miR signature.
Results: miR expression analysis on the training set of 20 aggressive and 19 indolent NHL yielded 80 significantly deregulated miRs. The 14 most significantly deregulated miRs (FDR<0.02) were analyzed on a validation set of 19 aggressive and 25 indolent NHL, yielding 9 validated miRs. Expression of these 9 miRs was determined on a set of 238 MCL cases. Following principal component analysis, the MCL cases were divided into 3 prognostic groups based on miR expression: a good group (median overall survival (OS):50.2 months), an intermediate group (median OS:37.5 months) and a poor group (median OS:9.4 months) (log rank p<0.0001). Using Ki67 cutoffs of 10 and 30% as reported in the literature on the same sample set was not significant (log rank p=0.5212).
Conclusions: We have discovered a miR signature that defines aggressiveness in NHL. This signature shows prognostic value in MCL and is independent of the Ki67 index.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 210, Monday Morning