Relationship between DICER1 mutations and immunotherapy biomarkers in solid tumors.

Abstract

2603 Background: Dicer1 functions as a tumor suppressor in mouse models. In humans, somatic mutations are associated with many cancers in adults, and patients with DICER1 syndrome with DICER1 germline mutations are susceptible to childhood cancers. DICER1 is the core caner-intrinsic CTL-evasion gene, especially positive correlate with innate anti-PD-1 resistance signature or IPRES signature and hERV expression which involved in sensitivity and resistance to ICIs. Nevertheless, the association between mutations in DICER1 and the Chinese patients, the relationship between DICER1 mutations with immunotherapy biomarkers are unknown. Methods: NGS and clinical data were collected from 10953 Western pan-cancer patients (TCGA cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 3514 Chinese pan-cancer patients (Chinese cohort). Both DICER1 mutation ratio and TMB were calculated on the two cohorts following the same criteria.DNA NGS testing (MSI-high vs low/stable (MSS)) in Chinese cohort were included. NGS data of 3514 patients who also detected PD-L1 expression from Chinese clinical dataset were analyzed to explore the association with mutation and PD-L1. The survival information was collected from 1661 pan-cancer patients to analyze the association between DICER1 mutation and efficacy of immunotherapy (MSKCC cohort). Results: In total, 2.91% (319/10953) patients in TCGA harbored DICER1 mutation; in the Chinese cohort, the DICER1 mutation ratio (2.67%, 94/3514) was similar to TCGA. The top 5 mutant DICER1-associated cancer types in Chinese cohort were lung cancer, colon adenocarcinoma, liver cancer, uterine corpus endometrial carcinoma, melanoma. In both cohorts, TMB level of mutation group was significantly higher than wild-type group (p < 0.001). The ration of mutation group in MSI-H (50%) and MSI-L (23.53%) was significantly higher than wild-type group in Chinese cohort (2.17%) (p < 0.001). In addition, the ratio of PD-L1 positive expression (≥1%) in mutation group (48.94%, 46/48) was significantly higher than wild-type in Chinese cohort (38.48%,1316/2104) (p < 0.05). The survival probability of mutation group was significantly longer than wild-type group in immunotherapy. Conclusions: The results indicated that DICER1 mutation was associated with a higher TMB, MSI-H and PD-L1 expression level in Chinese patients. Patients with DICER1 mutations may benefit more from ICIs.