MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas

• Published in: Blood advances Vol. 3; no. 3; pp. 375 - 383
• Main Authors: Nayyar, Naema, White, Michael D., Gill, Corey M., Lastrapes, Matthew, Bertalan, Mia, Kaplan, Alexander, D'Andrea, Megan R., Bihun, Ivanna, Kaneb, Andrew, Dietrich, Jorg, Ferry, Judith A., Martinez-Lage, Maria, Giobbie-Hurder, Anita, Borger, Darrell R., Rodriguez, Fausto J., Frosch, Matthew P., Batchelor, Emily, Hoang, Kaitlin, Kuter, Benjamin, Fortin, Sarah, Holdhoff, Matthias, Cahill, Daniel P., Carter, Scott, Brastianos, Priscilla K., Batchelor, Tracy T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2019; American Society of Hematology
• Subjects: B7-H1 Antigen - biosynthesis; B7-H1 Antigen - genetics; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - metabolism; Central Nervous System Neoplasms - pathology; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Female; Gene Dosage; Humans; Lymphoid Neoplasia; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Middle Aged; Mutation; Myeloid Differentiation Factor 88 - genetics; NF-kappa B - metabolism; Up-Regulation; Whole Exome Sequencing
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2018027672

The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted MYD88 sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified MYD88 mutation in 67% (42 of 63) of patients, CDKN2A biallelic loss in 44% (16 of 36), and CD79b mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, CDKN2A), with few areas of amplification. CD79b mutations were associated with improved progression-free and overall survival. We did not identify amplification at the PD-1/PD-L1 loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified MYD88 mutation and CDKN2A loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of PD-L1 amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions. [Display omitted]