AKT1 in Asia: A landscape analysis of 11,813 Chinese tumor samples.

Abstract

e15076 Background: AKT1 is a key gene of the PI3K/AKT/mTOR signalling pathway. The recent development of ATK1 targeting drug has shown great promise. It is thus important to understand the genomic landscape of AKT1 in a specific population. Methods: Sequencing data of 11,813 tumor samples collected in China were analyzed for AKT1 mutation status. Concomitant genomic aberrations were further analyzed in tumors with AKT1 mutations. Results: AKT1 mutations were observed in 173 of 11,813 tumor samples (1.46%). The most common cancer types in our study included cervical (5.17%), breast (5.15%), osteosarcoma (3.51%), brain (3.14%), head and neck (2.22%) and colorectal (2.02%). We included only the cancer types with more than 50 cases for analysis. Higher frequencies of AKT1 mutation were observed in several common cancers, including brain glioma (1.38% vs 0.67%), breast (5.15% vs 2.92%), cervical (5.17% vs 2.93%), head and neck (2.22% vs 0.95%) cancer in our study than reported in TCGA, but showed no statistically significant difference. The main common type of variation was SNV/Indel (67.63%), amplification (20.81%), deletion (11.56%), fusion (1.16%). Among SNV/Indel, E17K accounted for 32.9% of AKT1 mutations, Q79K only accounted for 0.79%. AKT1 E17K was more commonly found in breast (3.09%), brain (1.96%) and cervical (1.72%) cancer. There is no significant difference between wild type and AKT1 mutated groups in age and gender. III/IV patients were identified in 85.71% of AKT1 mutated group, which were significantly higher than that of wild type group (73.76%; p<0.05).MSI-H patients were identified in 12.16% of AKT1 mutated group, which were significantly higher than that of wild type group (1.8%; p<0.001). Frequencies of specific concomitant aberrations varied between AKT1 mutated and wild type groups. In AKT1 mutated groups, 57 genes are more frequently altered, and mainly enriched in PI3K-Akt signaling pathway (26, q= 2.97E-20, MAPK signaling pathway (count:20, q= 9.74E-15), Central carbon metabolism in cancer (19, q= 5.01E-25), EGFR tyrosine kinase inhibitor resistance (19, q= 3.36E-24). Conclusions: Higher frequencies of AKT1 mutation were observed in several common cancers, including cervical, breast, osteosarcoma, brain, head and neck and colorectal in our study. AKT1 E17K was more commonly found in breast, brain and cervical cancer. Given the fact that III/IV patients are more common in AKT1 mutated group, it coincides with AKT inhibitors therapeutic prospects in a variety of advanced malignant tumors. MSI-H patients are more common in AKT1 mutated group, and it provides possibility for immune checkpoint inhibitors combined with targeted signaling pathway therapy. The enrichment results of the common co-occurring genes with AKT1 in this study, further investigations are still needed.