Vitreoretinal lymphoma (VRL) is a rare but aggressive masquerade syndrome, which would be easily confused with uveitis. The diagnostic gold standard remains the pathologic examination of ocular specimen with invasiveness and low sensitivity. To improve the safety and accuracy of VRL diagnosis, alternative techniques using intraocular fluid (IOF) samples are emerging. In this study, we aimed to test the diagnostic value of genetic mutation analysis of circulating cell-free DNA (cfDNA) in IOF for VRL and exhibit the mutation profile for revealing the molecular characteristics of VRL. Twenty-three suspected VRL patients were selected as the training group, who had genetic mutation analysis using a panel containing 446 tumor-related genes. Another external cohort including 5 VRL patients and 5 uveitis patients was selected for further validation. In training group, all of VRL patients had obtained 23 (IQR 13.5, 36.0) cfDNA mutations in IOF (sensitivity 100%), and 2 out of 6 uveitis patients had one and four mutations respectively (specificity 67%). The latter were identified as clonal hematopoiesis mutations. In validation group, all of VRL patients were positive and all of uveitis patients were negative for mutation analysis (sensitivity and specificity 100%). VRL patients from the two groups were characterized by the high mutation frequencies of PIM1 (21/22, 90.91%), MYD88 (17/22, 77.27%), CD79B (11/22, 50.00%), ETV6 (11/22, 50.00%) and IRF4 (11/22, 50.00%), and 77.27% were MCD subtype with PI3K-Akt signaling pathway alternation. In conclusion, it demonstrated a new mini-invasive and feasible method for VRL diagnosis using a panel of 466 tumor-related genes.
A case of Conradi-Hünermann-Happle syndrome with typical clinical manifestations confirmed by genetic mutation analysis
