Identification of Genomic Biomarkers of Disease Progression and Survival in Primary CNS Lymphoma
The determination of the genetic subtypes of primary CNS lymphoma (PCNSL) and their relationship to differential chemo-immunotherapeutic response has not been established. There is a particular need for genomic biomarkers that identify patients with newly-diagnosed PCNSL at high risk of early progression and death. We applied targeted next-generation sequencing for detection of recurrent single nucleotide variants, copy number alterations and zygosity abnormalities in diagnostic specimens from 78 PCNSL patients treated with a standard methotrexate-based regimen, to identify prognostically significant molecular subgroups. All patients received induction immunochemotherapy and 44 proceeded to dose-intensive consolidation. Genomic aberrations at four loci were associated with 91% of lymphoma progression events and all 15 deaths: (1) chromosome 6p copy-neutral loss of heterozygosity (CN-LOH) or focal homozygous deletion (HD) at 6p21.3, and mutations of tumor suppressor genes (2) BTG1, (3) ETV6 and (4) TP53. Cox regression multivariate analysis demonstrated a high risk of progression in patients with aberrations at these loci. Genomic aberrations at these loci were also associated with significantly shorter survival. Lower expression of HLA-DR was associated with 6p CN-LOH/6p21.3 HD and inferior prognosis. These genomic aberrations identify a high-risk molecular subgroup that may inform risk stratification in PCNSL. Further elucidation of the mechanisms of therapeutic resistance associated with the high-risk genetic phenotype is requisite to facilitate precision medicine and progress in therapy.