Author:
Parker Helen,Mirandari Amatta,Oquendo Carolina Jaramillo,Duran-Ferrer Martí,Stevens Benjamin,Buermann Lara,Amarasinghe Harindra E.,Thomas Jaya,Kadalayil Latha,Carr Louise,Syeda Shama,Sakthipakan Methusha,Parry Marina,Davis Zadie,McIver-Brown Neil,Xochelli Aliki,Ennis Sarah,Scarfo Lydia,Ghia Paolo,Kalpadakis Christina,Pangalis Gerassimos,Rossi Davide,Wagner Simon,Ahearne Matthew,Seifert Marc,Plass Christoph,Weichenhan Dieter,Kimby Eva,Sutton Lesley-Ann,Rosenquist Richard,Forconi Francesco,Stamatopoulos Kostas,Salido Marta,Ferrer Ana,Thieblemont Catherine,Ljungström Viktor,Amini Rose-Marie,Oscier David,Walewska Renata,Rose-Zerilli Matthew J.J.,Gibson Jane,Martín-Subero José Ignacio,Oakes Christopher,Bryant Dean,Strefford Jonathan C
Abstract
AbstractThe epiCMIT (epigenetically-determined Cumulative MIToses) mitotic clock traces B-cell mitotic history via DNA methylation changes in heterochromatin and H3K27me3-containing chromatin. While high scores correlated with poor outcomes in CLL and MCL, its prognostic significance in SMZL remains unknown. Derived from 142 SMZL cases using DNA methylation microarrays, epiCMIT values were correlated with genomic, transcriptomic, and clinical data. EpiCMIT as a continuous variable was significantly higher in females (p=0.02), patients with IGHV1-2*04 allele usage (p<0001), intermediate IGHV somatic hypermutation load (97-99.9% identity,p=0.04), elevated mutational burden (25 vs. 17 mut/Mb,p=0.001), driver gene mutations [KLF2(p<0.001),NOTCH2(p<0.01),TP53(p=0.01),KMT2D(p<0.001)], and del(7q) (p=0.01). Negative correlation between epiCMIT and telomere length (r=-0.29p<0.001) supported the association between cumulated proliferation and telomere attrition. While univariate analysis highlighted epiCMIT as robust predictor of shorter treatment-free survival (TFS), multivariate analysis confirmed epiCMIT as an independent marker for shorter TFS. In summary, our matched multi-omic datasets facilitate the clinico-biological characterization of SMZL and introduces epiCMIT as a strong prognostic marker, identifying high-risk patients and predicting reduced treatment-free survival, hence providing a new tool for risk-adapted patient management.
Publisher
Cold Spring Harbor Laboratory