PREX2 mutation serves as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma.

Abstract

e21504 Background: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes. Previous work suggested that PREX2 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of function in melanoma is needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the PREX2 mutation in 3547 tumor tissue or plasma ctDNA samples (including 122 melanoma) from different patients, and the public database of TACG was also compared. Data from Snyder-64 study (n = 64, anti- CTLA-4 therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of PREX2 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 5.94 % (211 in 3547). Meanwhile, the frequency of PREX2 mutation in TCGA cohort was 5.06 % (555 in 10953). In melanoma datebase, the frequency of PREX2 mutation in 122 melanoma tumor tissue or plasma ctDNA samples from different patients was 6.55 % (78 in 122). Meanwhile, the frequency of PREX2 mutation in melanoma in TCGA cohort was 25.56 % (113 in 422). We further analyzed Kaplan-Meier curves from Snyder-64 study (n = 64, anti- CTLA-4 therapy). In Snyder-64 study melanoma cohort, mutation of PREX2 was associated with higher neoantigen load (P = 0.02) and higher mutation count (P = 0.0027) in melanoma. PREX2 mutation was associated with prolonged overall survival (OS) trend compared with PREX2 wt in melanoma cohort (P = 0.09). Conclusions: In our study, the frequency of PREX2 mutation in pan cancers and melanoma was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. PREX2 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma via upregulating neoantigen load and mutation count.