Molecular Characterization and Therapeutic Implications of MYD88 and CDKN2A in Primary CNS Lymphoma

MYD88L265P mutation and CDKN2A loss are among the earliest reported aberrations identified during clonal evolution in primary central nervous system lymphoma (PCNSL), suggesting their role as driver gene mutations critical to the tumorigenesis of this disease. There is no consensus on the relationship between these mutations and prognosis. This study analyzed the incidence of MYD88L265P mutation and CDKN2A homozygous deletion (HD) in PCNSL in relation to prognosis, and whether they could be potential therapeutic targets. Forty-one patients with intracranially localized diffuse large B-cell lymphomas (DLBCL) with known prognosis were included; MYD88L265P mutation was determined using i-densy, MYD88 protein expression using immunostaining, and CDKN2A HD using fluorescence in situ hybridization (FISH). Overall survival (OS) was calculated using the Kaplan-Meier method. MYD88L265P mutation was found in 35% (7/20) of patients, with a median OS of 14 and 29 months in the mutation-positive and mutation-negative groups, respectively; this was shorter in the mutation-positive group (p= 0.6). Immunostaining was positive in 85% (34/40); median OS was 22 and 28.5 months in the immunostaining-positive and immunostaining-negative groups, respectively; this was shorter in the positive group (p=0.4). CDKN2A HD was found in 73% (27/37) of patients, with median OS of 15 and 35 months, in the HD-positive and HD-negative groups, respectively; shorter in the HD -positive group (p=0.3). When the MYD88L265P mutation and CDKN2A HD were analyzed together, there was a trend toward shorter survival in the group with both mutations (p=0.8). The MYD88L265P mutation was present in 35% of patients, and CDKN2A HD was present in 73%. The MYD88L265 mutation and CDKN2A HD, when considered separately, did not individually demonstrate a clear prognostic correlation; however, prognosis varied notably between patients presenting with both mutations compared to those without. The presence or absence of these mutations may be helpful in future treatment selection when the disease becomes relapsed/refractory after initial therapy.