Follicular Lymphoma Multiomics Project (FLOMICS) - integrating data from targeted DNA sequencing, methylome profiling, and bulk RNAseq to discover new subtypes
Molecular classification or subtyping of cancers is becoming an essential step toward the clinical practice of precision medicine. In follicular lymphoma (FL), molecular classification or subtyping has emerged as a major unmet need. This project focuses on the analysis of multi-omics data to subclassify FL. The project aims to study gene mutations, the transcriptome and the methylome of FL, to rigorously define and validate molecular subtypes by unravelling inter- and intra-patient heterogeneity. Our hypothesis is that FL is not just one disease, but that it can be classified into biologically distinct subgroups.
Follicular lymphoma (FL), the most prevalent indolent non-Hodgkin lymphoma, exhibits considerable variability in biological features and clinical trajectories across patients. Despite an increased understanding of its genetic basis, a definitive molecular taxonomy has yet to be established. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Additionally, we conducted an assessment of methylomic and immunoglobulin isotype profiles to comprehensively characterize the genetic subtypes. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with distinct clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and was associated with a lower proliferative history compared to the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Collectively, our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.