IDENTIFICATION OF GENOMIC BIOMARKERS OF DISEASE PROGRESSION AND SURVIVAL IN NEWLY‐DIAGNOSED PRIMARY CNS LYMPHOMA

Abstract

Introduction: There is a significant unmet need for robust genomic biomarkers that identify patients with newly-diagnosed primary CNS lymphoma (PCNSL) at high risk of progression, both during standard methotrexate-based induction as well as after dose-intensive consolidation. Methods: We performed targeted next-generation sequencing of 529 cancer genes of formalin-fixed, paraffin-embedded tumors from 74 patients with newly diagnosed primary CNS diffuse large B-cell lymphoma using the UCSF500 Cancer Panel and the Institute for Human Genetics CLIA Laboratory. The assay detects structural variants including single nucleotide variants, small insertions and deletions, and copy-number alterations (CNAs). Sixty-four EBV-negative PCNSL patients treated with a standard methotrexate, temozolomide, rituximab (MTR) induction were available for complete analysis. Results: We identified frequent mutations involving MYD88 (77%), CD79B (41.9%), ETV6 (27%) and BTG1 (25.7%) as well as frequent CNA involving 6q loss (62.5%), 9p loss (34.4%) and 12 gain (31.3%). Three genomic alterations were most significantly associated with early disease progression in PCNSL: (1) Alterations at 6p21.3, predominantly copy neutral loss of heterozygosity (CN-LOH) at the HLA Class I (HLA-A, B, C) and Class II loci (HLA-DR, DP, DQ, TAP1) as well as homozygous deletion of HLA Class II; (2) Mutations of tumor suppressor genes BTG1 and ETV6. Overall, these genomic alterations were detected in 28 out of 31 progression events in the cohort. The subgroup with either CN-LOH or homozygous deletion at 6p had the earliest progression, followed by the subgroup with mutations at either BTG1/ETV6 and no 6p CN-LOH or homozygous deletion, compared to no alterations at these 3 loci. 10 of 18 tumors with these alterations at 6p also contained BTG1 and/or ETV6 mutations. Survival analysis demonstrates that the subgroup with 6p CN-LOH or homozygous deletion had the earliest progression, followed by the subgroup with BTG1/ETV6 mutations compared to no alterations at these 3 loci (PFS p = 3.7e-5, OS p = 0.0017, logrank test, Figure 1). Multivariate Cox proportional hazard analysis demonstrated a significant 3.24-fold increased risk of progression with 6p CN-LOH/homozygous deletion or BTG1/ETV6 mutations (p = 3.5e-5, adjusted by Age, KPS, IELSG, MSKCC, IOL, Maintenance, and Consolidation). The research was funded by: National Cancer Institute NIH R01CA139-83-01A1 Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, genomics, epigenomics, and other-omics No conflicts of interests pertinent to the abstract.