Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer

INTRODUCTION: Gastric cancer (GC)is the third leading cause of cancer-related deaths in China and immunotherapy emerging as a revolutionary treatment for GC recently. Tumor mutational burden (TMB) is a predictive biomarker of immunotherapy in multiple cancers. However, the prognostic significance and subtype of TMB in GC is not fully understood. OBJECTIVES: This study aims to evaluate the prognostic value of TMB in Chinese GC and further classify TMB-high GC (GC(TMB-H)) patients combing with mutational signatures. METHODS: Genomic profiling of 435 cancer-gene panel was performed using 206 GC samples from Chinese people. Actionable genetic alterations were compared across all the samples to generate actionable subtyping. The prognostic value of TMB in Chinese GC was evaluated. Mutational signatures were analyzed on TMB-H subtype to stratify the prognosis of TMB. Transcriptomic analysis was applied to compare the distributed immunocytes among different subtypes. RESULTS: 88.3% (182/206) of GC samples had at least one mutation, while 45.1% (93/206) had at least one somatic copy number alteration (SCNA). 29.6% (61/206) of GC samples were TMB-H, including 13 MSI-H and 48 MSS tumors. According to distinct genetic alteration profiles of 69 actionable genes, we classified GC samples into eight molecular subtypes, including TMB-H, ERBB2 amplified, ATM mutated, BRCA2 mutated, CDKN2A/B deleted, PI3KCA mutated, KRAS mutated, and less-mutated subtype. TMB-H subtype presented a remarkable immune-activated phenotype as determined by transcriptomic analysis that was further validated in the TCGA GC cohort. GC(TMB-H) patients exhibited significantly better survival (P = 0.047). But Signature 1-high GC(TMB-H) patients had relatively worse prognosis (P = 0.0209, HR = 2.571) than Signature 1-low GC(TMB-H) patients from Chinese GC cohort, also validated in TCGA GC cohort, presenting highly activated carbohydrate, fatty acid or lipid metabolism. CONCLUSION: The Signature 1-high GC(TMB-H) could be a marker of poor prognosis and is associated with metabolism disorder.