Integrative genomic and transcriptomic analysis reveals genetic alterations associated with the early progression of follicular lymphoma

Abstract

Introduction: Follicular lymphoma (FL), the most common indolent lymphoma, is a clinically and genetically heterogeneous disease. Progression of disease within 24 months (POD24) is strongly associated with poor outcome. Therefore, prediction of POD24 at diagnosis is essential to support the precision medicine treatment strategies making in clinical practice. However, risk factors associated with POD24 remain uncertain in FL patients. In addition, the prognostic value of driver gene mutations and copy number alterations has not been systematically assessed in FL. Method: We analysed clinical-biological features of 415 FL patients to identify variables associated with POD24. In addition, we integrated whole exome sequencing (WES) and transcriptomic analysis of 102 these patients with FL to identify genetic alterations associated with early progression. Result: POD24 occurred in 21% of evaluable FL patients, with a 5-year OS rate of 82.9% compared with 96.2% for those without POD24 (HR, 5.03; 95% CI, 2.15–11.72; P < 0.01). Patients with B symptoms, elevated lactate dehydrogenase and β2-microglobulin levels, unfavourable baseline haemoglobin levels, advanced stage, and high-risk FL International Prognostic Index (FLIPI) scores had an increased risk of POD24, with FLIPI being the most important factor in logistic regression. Among all the somatically occurring non-silent mutations, twenty-three genes were considered cancer drivers. HIST1H1D, known as a driver mutation, was significantly correlated with POD24. Gains of 6q22.2 (HIST1H1D) and 18q21.33 (BCL2) and loss of 1p36.13 (NBPF1) predicted POD24 independent of FLIPI. Integration of the four variants led to the identification of 76% of POD24 patients. Gene expression profiling (GEP) of 41 FL samples showed that the POD24 cohort was significantly enriched in the inflammatory response (mediated by interferon and tumour necrosis factor) and cell cycle regulation (transcription, replication and proliferation) sets. Keywords: Diagnostic and Prognostic Biomarkers, Genomics, Epigenomics, and Other -Omics, Indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.