Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma

Abstract

Follicular lymphoma (FL) is an incurable B-cell malignancy characterized by advanced stage disease and a heterogeneous clinical course, with high-risk groups including those that transform to an aggressive lymphoma, or progress early (within 2 years) following treatment. Recent sequencing studies have established the diverse genomic landscape and the temporal clonal dynamics of FL [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]; however, our understanding of the degree of spatial or intra-tumor heterogeneity (ITH) that exists within an individual patient is limited. In contrast, multi-site profiling in solid organ malignancies has demonstrated profound ITH impacting mechanisms of drug resistance and compromising precision-medicine-based strategies to care [ 8 ]. In FL, the rise in trials adopting targeted therapies such as EZH2, PI3K, and BTK inhibitors reflects this paradigm shift in cancer care and with the development of biomarker-driven studies highlights the need to accurately define genomic alterations with clinical relevance. As most FL patients manifest disseminated tumor involvement, we sought to uncover the extent and clinical importance of spatial heterogeneity in FL by using a combination of whole-exome and targeted deep sequencing (Supplementary methods).