Genome sequencing of lymphoid malignancies.

Source

Department of Pathology and the Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, United States.

Abstract

Our understanding of the pathogenesis of lymphoid malignancies has been transformed by the advent of next generation sequencing. These studies 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 and the lymphomas. While each tumor type is characterized by a unique genomic landscape, a remarkable finding from these studies is the involvement of specific cellular pathways across multiple tumors types - such as the transcriptional regulation of differentiation, antigen receptor signaling, tyrosine kinase and Ras signaling, and epigenetic modifications - and the identification of individual genes as targets of mutation 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-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.

TimAllenMDJD

Wednesday, September 18, 2013