Assessment Of Regulation Of Rhoa Activity Panel Mutations As A Predictive Biomarker In Patients With Gastric Cancer

Abstract Background: Although histological and molecular classifications have been established for gastric cancer (GC), the clinical application of their prognostic and therapeutic values is still limited. RHOA is one of the well-known members of the RHO-family GTPase and associated with the essential functions of GC. Here we identified a predictive biomarker “regulation of RhoA activity panel (RRAP)” and assessed its potential clinical significance in patients with GC. Methods: A cohort of The Cancer Genome Atlas database (TCGA) gastric samples was split into training and validation set to develop and test a biomarker RRAP by genetic algorithm. We performed an independent validation of RRAP on a cohort of 109 Chinese gastric cancer (CGC) patients measured by whole-exome sequencing (WES). To explored the underlying relationship between RRAP and clinical outcomes, we evaluated the metastasis capacity and tumor immune microenvironment (TIME) signatures of RRAP. Another independent cohort of 37 patients with metastatic GC was used to investigate the efficacy of RRAP in distinguishing patients who would benefit from immunotherapy. Results: We designed RRAP by genetic algorithm to develop optimal prognostic 20 mutated genes in training cohort. The patients were classified as RRAP-wildtype group or RRAP-mutated group according to whether mutation(s) occur in coding region of any of those 20 genes. RRAP classifier was significantly associated with prognosis in TCGA training, TCGA validation, and independent CGC cohort. RRAP-mutated patients were associated with a better prognosis than RRAP-wildtype patients (TCGA training: hazard ratio, 0.40; 95% CI, 0.20-0.79; log-rank P = 0.006; TCGA validation: hazard ratio, 0.48; 95% CI, 0.26-0.91; log-rank P = 0.021; CGC: hazard ratio, 0.13; 95% CI, 0.03-0.52; log-rank P = 6.66e-04). We observed that RRAP-mutated tumors had a lower degree of lymph nodes metastasis and lower activity in migration-related pathways. Meanwhile, we found that RRAP-mutated tumors had higher lymphocyte infiltration and cytotoxic activity to modulate the TIME of GC, indicating RRAP may be a potential predictive biomarker for immune checkpoint blockade (ICB) therapy. The clinical benefit rate of RRAP mutated patients was higher than RRAP-wildtype (57.1% vs 33.3%) in the independent immunotherapy cohort. Conclusions: We proved the RRAP to be a potential predictive biomarker for prognosis and therapeutic selection with different tumor cell migration capacity and TIME signatures, which may account for the association of RRAP and phenotype. Citation Format: Wenwen Huang, Songhui Zhao, Cheng Zhang, Jing Gao, Weiwei Shi, Lin Shen. Assessment of regulation of RhoA activity panel mutations as a predictive biomarker in patients with gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1136.