Genome sequencing of lymphoid malignancies.

Our understanding of the pathogenesis of lymphoid malignancies has been transformed by next-generation sequencing. The studies in this review have used whole-genome, exome, and transcriptome sequencing to identify recurring structural genetic alterations and sequence mutations that target key cellular pathways in acute lymphoblastic leukemia (ALL) and the lymphomas. Although each tumor type is characterized by a unique genomic landscape, several cellular pathways are mutated in multiple tumor types-transcriptional regulation of differentiation, antigen receptor signaling, tyrosine kinase and Ras signaling, and epigenetic modifications-and individual genes are mutated in multiple tumors, notably TCF3, NOTCH1, MYD88, and BRAF. In addition to providing fundamental insights into tumorigenesis, these studies have also identified potential new markers for diagnosis, risk stratification, and therapeutic intervention. Several genetic alterations are intuitively "druggable" with existing agents, for example, kinase-activating lesions in high-risk B-cell ALL, NOTCH1 in both leukemia and lymphoma, and BRAF in hairy cell leukemia. Future sequencing efforts are required to comprehensively define the genetic basis of all lymphoid malignancies, examine the relative roles of germline and somatic variation, dissect the genetic basis of clonal heterogeneity, and chart a course for clinical sequencing and translation to improved therapeutic outcomes.