Author:
Thomas Nicole,Dreval Kostiantyn,Gerhard Daniela S.,Hilton Laura K.,Abramson Jeremy S.,Bartlett Nancy L.,Bethony Jeffrey,Bowen Jay,Bryan Anthony C.,Casper Corey,Cruz Manuela,Dyer Maureen A.,Farinha Pedro,Gastier-Foster Julie M.,Gerrie Alina S.,Grande Bruno M.,Greiner Timothy,Griner Nicholas B.,Gross Thomas G.,Harris Nancy L.,Irvin John D.,Jaffe Elaine S.,Leal Fabio E.,Martin Jean Paul,Martin Marie-Reine,Mbulaiteye Sam M.,Mullighan Charles G.,Mungall Andrew J.,Mungall Karen,Namirembe Constance,Noy Ariela,Ogwang Martin D.,Orem Jackson,Ott German,Petrello Hilary,Reynolds Steven J.,Slack Graham,Soudi Shaghayegh,Swerdlow Steven H.,Traverse-Glehen Alexandra,Wilson Wyndham H.,Wong Jasper,Marra Marco A.,Staudt Louis M.,Scott David W.,Morin Ryan D.
Abstract
AbstractBurkitt lymphoma (BL) accounts for the majority of pediatric non-Hodgkin lymphomas (NHL) and is relatively rare but significantly more lethal when diagnosed in adults. The global incidence is highest in Sub-Saharan Africa, where Epstein-Barr virus (EBV) positivity is observed in 95% of all tumors. Both pediatric (pBL) and adult (aBL) cases are known to share some driver mutations, for example MYC translocations, which are seen in > 90% of cases. Sequencing efforts have identified many common somatic alterations that cooperate with MYC in lymphomagenesis with approximately 30 significantly mutated genes (SMG) reported thus far. Recent analyses revealed non-coding mutation patterns in pBL that were attributed to aberrant somatic hypermutation (aSHM). We sought to identify genomic and molecular features that may explain clinical disparities within and between aBL and pBL in an effort to delineate BL subtypes that may allow for the stratification of patients with shared pathobiology. Through comprehensive sequencing of BL genomes, we found additional SMGs, including more genetic features that associate with tumor EBV status, and established three new genetic subgroups that span pBL and aBL. Direct comparisons between pBL and aBL revealed only marginal differences and the mutational profiles were consistently better explained by EBV status. Using an unsupervised clustering approach to identify subgroupings within BL and diffuse large B-cell lymphoma (DLBCL), we have defined three genetic subgroups that predominantly comprise BL tumors. Akin to the recently defined DLBCL subgroups, each BL subgroup is characterized by combinations of common driver mutations and non-coding mutations caused by aSHM. Two of these subgroups and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among the aBL and pBL cohorts. These findings highlight not only a shared pathogenesis between aBL and pBL, but also establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiological studies, and diagnostic and therapeutic strategies.
Publisher
Cold Spring Harbor Laboratory