Genomic and transcriptomic profiling of inflammatory breast cancers and non-inflammatory breast cancers in Asian women.

Abstract

e12546 Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Despite its rare incidence, it accounts for 10% of breast cancer-caused mortality. Previous studies based on NGS have focused on western populations and found no common genomic and transcriptomic difference that could distinguish IBC from non-IBC. Methods: We performed WES on 15 IBC samples and their paired normal blood to identify somatic genomic alterations, copy number variants and large structural variants. RNA-seq was performed on 16 IBC samples to examine the RNA expression, pathway enrichment and gene fusions. WES and RNA-seq data were further investigated to discover genes that were dysregulated in both genomics and transcriptomics. For comparison, we performed WES and RNA-seq on 5 non-IBC samples and acquired additional 33 non-IBC samples of Asian women from the Cancer Genome Atlas Program (TCGA). Results: Apart from results similar to the previous reports in western IBC, ZNF74 and DYNC2H1 were identified as Asian-IBC-specific somatic mutations in our cohort. Elevated HRD mutational signature and scarHRD score indicated increased HRD events in Asian IBC patients. Structural variation analysis showed that deletions were found more frequent in IBC. RNA-seq indicated increased immune activation in IBC samples, but the immune cell infiltration within the tumor microenvironment were similar between IBC and non-IBC. Multiple gene fusions were more frequently found in IBC, including CTC-786C10.1—RP11-680G10.1, TULP4—RP11-732M18.3, RN7SL4P—RN7SL173P. Combined analysis of WES and RNA-seq showed more frequent mutation and increased pathway enrichment of RAS pathway in IBC, which may explain the aggressive biological behavior of IBC, inhibitors such as sorafenib, tipifarnib and trametinib targeting RAS signaling and its downstream pathways were predicted to possess promising effects in IBC treatment. Conclusions: Our study is the first to provide a complete genomic and transcriptomic landscape of IBC based on combined analysis of WES and RNA-seq and the first to focus on Asian women. We discovered intriguing differences unique in Asian women that could potentially explain IBC etiology and presented RAS signaling pathway as a potential therapeutic target in IBC treatment.