The tumour microenvironment influences survival and time to transformation in follicular lymphoma in the rituximab era
BRITISH JOURNAL OF HAEMATOLOGY
Authors: Blaker, Yngvild Nuvin; Spetalen, Signe; Brodtkorb, Marianne; Lingjaerde, Ole Christian; Beiske, Klaus; Ostenstad, Bjorn; Sander, Birgitta; Wahlin, Bjorn Engelbrekt; Melen, Christopher Michael; Myklebust, June Helen; Holte, Harald; Delabie, Jan; Smeland, Erlend Bremertun
Abstract
The tumour microenvironment influences outcome in patients with follicular lymphoma (FL), but its impact on transformation is less studied. We investigated the prognostic significance of the tumour microenvironment on transformation and survival in FL patients treated in the rituximab era. We examined diagnostic and transformed biopsies from 52 FL patients using antibodies against CD3, CD4, CD8, CD21 (CR2), CD57 (B3GAT1), CD68, FOXP3, TIA1, PD-1 (PDCD1), PD-L1 (CD274) and PAX5. Results were compared with a second cohort of 40 FL patients without signs of transformation during a minimum of five years observation time. Cell numbers and localization were semi-quantitatively assessed. Better developed CD21+ follicular dendritic cell (FDC) meshworks at diagnosis was a negative prognostic factor for overall survival (OS), progression-free survival (PFS) and time to transformation (TTT) in patients with subsequently transformed FL. Remnants of FDC meshworks at transformation were associated with shorter OS and PFS from transformation. High degrees of intrafollicular CD68+ and PD-L1+ macrophage infiltration, high total area scores and an extrafollicular/diffuse pattern of FOXP3+ T cells and high intrafollicular scores of CD4+ T cells at diagnosis were associated with shorter TTT. Scores of several T-cell subset markers from the combined patient cohorts were predictive for transformation, especially CD4 and CD57.
Defining the genetic control of human blood plasma N-glycome using genome-wide association study
HUMAN MOLECULAR GENETICS
Authors: Sharapov, Sodbo Zh.; Tsepilov, Yakov A.; Klaric, Lucija; Mangino, Massimo; Thareja, Gaurav; Shadrina, Alexandra S.; Simurina, Mirna; Dagostino, Concetta; Dmitrieva, Julia; Vilaj, Marija; Vuckovic, Frano; Pavic, Tamara; Stambuk, Jerko; Trbojevic-Akmacic, Irena; Kristic, Jasminka; Simunovic, Jelena; Momcilovic, Ana; Campbell, Harry; Doherty, Margaret; Dunlop, Malcolm G.; Farrington, Susan M.; Pucic-Bakovic, Maja; Gieger, Christian; Allegri, Massimo; Louis, Edouard; Georges, Michel; Suhre, Karsten; Spector, Tim; Williams, Frances M. K.; Lauc, Gordan; Aulchenko, Yurii S.
Abstract
Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area.
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