title: Differential gene expression in non-malignant tumour microenvironment is associated with outcome in follicular lymphoma patients treated with rituximab and CHOP.
abstract: Rituximab in combination with chemotherapy (immunochemotherapy) is one of the most effective treatments available for follicular lymphoma (FL). This study aimed to determine whether differences in gene expression in FL tissue correlate with outcome in response to rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (R-CHOP). We divided 24 patients into long- [time to treatment failure (TTF) >35 months] and short-term (TTF <23 months) responders, and analysed the gene expression profiles of lymphoma tissue using oligonucleotide microarrays. We used a supervised learning technique to identify genes correlating with outcome, and confirmed the expression of selected genes with quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Among the transcripts with a high correlation between microarray and qPCR analyses, we identified EPHA1, a tyrosine kinase involved in transepithelial migration, SMAD1, a transcription factor and a mediator of bone morphogenetic protein and transforming growth factor-beta signalling, and MARCO, a scavenger receptor on macrophages. According to Kaplan-Meier estimates, high EPHA1, and low SMAD1 and MARCO expression were associated with better progression-free survival (PFS). Immunohistochemistry showed that EphA1 was primarily localised in granulocytes. In addition, both EphA1 and Smad1 were expressed in vascular endothelia. However, no difference in vasculature was detected between long- and short-term responders. In a validation set of 40 patients, a trend towards a better PFS was observed among patients with high EphA1 expression. We conclude that gene expression in non-malignant cells contributes to clinical outcome in R-CHOP-treated FL patients.
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Harjunpää
authors.forename: Minna
authors.initials: M
authors.lastname: Taskinen
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Karjalainen-Lindsberg
authors.forename: Heidi
authors.initials: H
authors.lastname: Nyman
authors.forename: Outi
authors.initials: O
authors.lastname: Monni
authors.forename: Samuli
authors.initials: S
authors.lastname: Hemmer
authors.forename: Olli
authors.initials: O
authors.lastname: Yli-Harja
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
authors.forename: Sirpa
authors.initials: S
authors.lastname: Leppä
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010865:Pilot Projects; D016133:Polymerase Chain Reaction / Q000379:methods; D011241:Prednisone / Q000008:administration & dosage; D036082:Receptor, EphA1 / Q000378:metabolism; D000069283:Rituximab; D051785:Smad Proteins / Q000378:metabolism; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D051785:Smad Proteins; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D036082:Receptor, EphA1; D011241:Prednisone