Tumor mutation burden and immunogenicity in gastric cancer with HER2 alterations.

Abstract

4024 Background: Human epidermal growth receptor 2 (HER2) is considered as an oncogenic driver gene in gastric cancer (GC). Immunotherapy has been proven to be effective in GC patients. Previous studies indicated that patients harboring driver mutations were considered as poor candidate for immunotherapy. But the efficacy of immunotherapy for HER2 positive GC has not been defined. We therefore analyzed the immunogenicity of HER2 alterations in GC. Methods: Genomic profiling of DNA from 448 GC was performed using next-generation sequencing on 381 cancer associated genes. The expression of PD-L1 protein was evaluated in 192 GC with the use of an automated immunohistochemical assay (Ventana, SP263). Whole-exome sequencing, copy number variations, RNA-seq and clinical data of 443 GC from The Cancer Genome Altas (TCGA) were also analyzed to further evaluate the immunogenicity of HER2 alterations. TMB was defined as number of somatic non-synonymous mutations in coding regions. HER2 amplification in TCGA was defined as “2” derived from the copy-number analysis algorithms GISTIC. Results: HER2 alterations including amplification, missense and fusion were present in 19.2% (85/443) of TCGA cohort and 11.4% (51/448) of clinical cohort. 14.0% (62/443) of TCGA cohort and 6.0% (27/448) of clinical cohort harbored HER2 amplification. Higher TMB was observed in MSS/MSI-L patients carrying any HER2 alterations in TCGA cohort (P = 0.009). On the contrary, HER2 alterations did not show a higher neoantigen level and HER2 alterations were associated with decreased immunogenicity in terms of immune-related gene mRNA expression and immune infiltrates. In clinical cohort, HER2 alterations was also significantly associated with higher TMB (P = 0.001). Meanwhile, a trend of shrinking proportion of PD-L1 expression was observed in HER2 alteration subgroup (2/23, 8.7%) than HER2 wild-type subgroup (47/169, 27.8%, P = 0.071). Furthermore, HER2 amplification had significant positive associations with HRD score (P = 0.0169) in TCGA cohort which indicated an increased degree of genome instability. Conclusions: Although HER2 alterations in GC were associated with increased TMB, HER2 alterations exhibited poor immunogenicity. These findings indicated that HER2 alterations might confer resistance to immune monotherapy.