FAT4 mutation serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma.

Abstract

e21553 Background: FAT4 functions as a tumor suppressor, and previous findings have demonstrated that FAT4 can inhibit the epithelial-to-mesenchymal transition (EMT) and the proliferation of gastric cancer cells. FAT4 is involved in the maintenance of PCP and inhibition of cell proliferation. FAT4 mRNA is repressed in breast cancer and lung cancer due to promoter hypermethylation. FAT4 gene is recurrently mutated in several types. Previous work suggested that FAT4 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 FAT4 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 Miao-249 study (n = 151, anti-PD-(L)1/CTLA-4 mono/ combined 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 FAT4 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 8.11 % (288 in 3547). Meanwhile, the frequency of FAT4 mutation in TCGA cohort was 10.08 % (1105 in 10953). In melanoma datebase, the frequency of FAT4 mutation in 122 melanoma tumor tissue or plasma ctDNA samples from different patients was 5.73 % (7 in 122). Meanwhile, the frequency of FAT4 mutation in melanoma in TCGA cohort was 38.2 % (169 in 422) We further analyzed Kaplan-Meier curves from Miao-249 study (n = 151, anti-PD-(L)1/CTLA-4 mono/ combined therapy). In Miao-249 melanoma cohort, mutation of FAT4 was associated with higher TMB (P = 0.032) and higher mutation count (P = 0.003) in melanoma. FAT4 mutation was associated with prolonged overall survival (OS) compared with FAT4 wt in melanoma (P = 0.0478). Conclusions: In our study, the frequency of FAT4 mutation in pan cancers and melanoma was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. FAT4 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma via upregulating TMB and mutation count.