TY - JOUR
T1 - Targetable genetic features of primary testicular and primary central nervous system lymphomas
AU - Chapuy, Bjoern
AU - Roemer, Margaretha G. M.
AU - Stewart, Chip
AU - Tan, Yuxiang
AU - Abo, Ryan P.
AU - Zhang, Liye
AU - Dunford, Andrew J.
AU - Meredith, David M.
AU - Thorner, Aaron R.
AU - Jordanova, Ekaterina S.
AU - Liu, Gang
AU - Feuerhake, Friedrich
AU - Ducar, Matthew D.
AU - Illerhaus, Gerald
AU - Gusenleitner, Daniel
AU - Linden, Erica A.
AU - Sun, Heather H.
AU - Homer, Heather
AU - Aono, Miyuki
AU - Pinkus, Geraldine S.
AU - Ligon, Azra H.
AU - Ligon, Keith L.
AU - Ferry, Judith A.
AU - Freeman, Gordon J.
AU - van Hummelen, Paul
AU - Golub, Todd R.
AU - Getz, Gad
AU - Rodig, Scott J.
AU - de Jong, Daphne
AU - Monti, Stefano
AU - Shipp, Margaret A.
PY - 2016/2/18
Y1 - 2016/2/18
N2 - Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL
AB - Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL
U2 - https://doi.org/10.1182/blood-2015-10-673236
DO - https://doi.org/10.1182/blood-2015-10-673236
M3 - Article
C2 - 26702065
SN - 0006-4971
VL - 127
SP - 869
EP - 881
JO - Blood
JF - Blood
IS - 7
ER -