Research Article: Extracellular Tumor-Related mRNA in Plasma of Lymphoma Patients and Survival Implications

Date Published: December 15, 2009

Publisher: Public Library of Science

Author(s): Vanesa Garcia, Jose Miguel Garcia, Javier Silva, Paloma Martin, Cristina Peña, Gemma Dominguez, Raquel Diaz, Mercedes Herrera, Constanza Maximiano, Pilar Sabin, Antonio Rueda, Miguel Angel Cruz, Jose Rodriguez, Miguel Angel Canales, Felix Bonilla, Mariano Provencio, Patrick Tan.

Abstract: We studied anomalous extracellular mRNAs in plasma from patients with diffuse large B-cell lymphoma (DLBCL) and their survival implications. mRNAs studied have been reported in the literature as markers of poor (BCL2, CCND2, MYC) and favorable outcome (LMO2, BCL6, FN1) in tumors. These markers were also analyzed in lymphoma tissues to test possible associations with their presence in plasma.

Partial Text: DLBCL accounts for approximately 30% of new diagnoses and more than 80% of aggressive lymphomas. Recently, anti-CD20 monoclonal antibody (rituximab) has been combined with CHOP, which has improved survival [1]. DLBCL is a non-uniform subgroup of tumors with a variety of clinical presentations, outcomes, response to treatment and genetic alterations. This could be because DLBCL consists of several diseases, but stratification into subclasses by standard pathologic techniques has not been possible. Thus, studies about individual prognostic markers and prognostic models based on the combination of several markers have been performed, so increasing the insights of molecular heterogeneity [2]. There is disparity between the genes that comprise the predictive models of the studies, which could be due to different criteria for patient selection and statistical algorithms used for their construction [2]. In an attempt to devise a technically simple model, Lossos and colleagues evaluated 36 genes found to be predictive of outcome in gene array studies and created a prediction model validated in these previous studies [3].

LMO2, BCL6 and FN1 mRNA in lymphoma correlated with prolonged survival [2], but when we detected them in plasma, no differences with healthy controls or associations with favorable outcome were found, except for LMO2 mRNA. This could be explained because the release of free nucleic acids into plasma for tumor cells is a characteristic of poor outcome, which might overcome the good prognostic value of these mRNA within the lymphoma cells. When we studied mRNA in plasma of poor-prognosis genes in tumors (MYC, CCND2 and BCL2) [2], patients with presence of these mRNA in plasma have clinical and biochemical features indicative of poor prognosis and short survival. These results suggest that unfavorable molecular markers described in tumors [2], mainly MYC mRNA, could similarly be markers of poor outcome if they are found in plasma. Our results suggested that the markers found in plasma from DLBCL relating to poor outcome had lower prognostic value in B-cell lymphoma with slow proliferation (FL) and, overall, with HL.



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