The diagnosis of vitreoretinal lymphoma (VRL), a rare subtype of primary central nervous system lymphoma (PCNSL), is challenging. We aimed to investigate the mutational landscape of VRL by sequencing circulating tumor DNA (ctDNA) from aqueous humor (AH) and/or vitreous fluid (VF), as well as the application of ctDNA sequencing to diagnosis and treatment monitoring. Baseline AH and/or VF specimens from 15 VRL patients underwent comprehensive genomic profiling using targeted next-generation sequencing. The molecular profiles of paired baseline AH and VF specimens were highly concordant, with comparable allele frequencies (AFs). However, the genetic alterations detected in cerebrospinal fluid (CSF) ctDNA only partially overlapped with those from simultaneously-collected AH/VF samples, with much lower AFs. Serial post-treatment AH or VF samples were available for five patients and their ctDNA AF changes displayed a similar trend as the changes in interleukin 10 (IL-10) levels; an indicator of treatment responses. A cohort of 23 PCNSL patients was included as a comparison group for the genetic landscape and evaluations of the efficacy of ibrutinib. More MYD88 mutations, but fewer IRF4 mutations and CDKN2A/B copy number losses were observed in the baseline samples of PCNSL than VRL patients. The objective response rate of ibrutinib treatment was much higher for PCNSL patients (64.7%, 11/17) than VRL (14.3%, 1/7) patients. In summary, we provided valuable clinical evidence that AH is a good source of tumor genomic information and can be substituted for VF. Moreover, molecular profiling of AH has clinical utility for the diagnosis of VRL and treatment monitoring.
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