Abstract PD6-06: Somatic mutation patterns differentially affect survival in breast cancer molecular subtypes

Abstract

Abstract Background: The prognostic effects of somatic gene mutations and correlated gene expression in breast cancer is argument of debate. In this study we analyzed the impact of specific mutations on gene expression and their relevance in the prognosis of breast cancer subtypes. Materials and methods: Exome sequencing and RNA-seq data obtained from TCGA were analyzed. Data was processed using MuTect, MapSplice and RSEM. All together data from 757 patients (ER-/HER2- [n=143], HER2+ including ER positive and negative patients, [n=136], and ER+/HER2- [n=478]) were included. Univariate Receiver Operating Characteristic (ROC) analysis was performed for the top mutated genes (mutated in at least 5% of patients) using the ROC Bioconductor library in R to identify genes whose expression was significantly associated with a mutation. Then, the mean expression of the significant genes was designated as a metagene for each genotype. We assessed the correlation with survival for each metagene by Cox proportional hazards regression and by plotting Kaplan-Meier survival plots. A significance threshold of p<1E-04 was set for each gene to be considered in the survival analysis, and only the top 100 genes were used when there were more than 100 genes significant. Results: In the overall population only few mutated genes including TP53 (HR=1.66), CDH1 (HR=0.61), AKT1 (HR=0.54), ATM (HR=1.76), NF1 (HR=0.58), KMT2D (HR=2.32), and UBR5 (HR=1.94) were significantly associated with survival. In ER-/HER2- mutant samples the PIK3CA (HR=2.79) and MAP3K1 (HR=2.98), and in HER2+ mutant samples the ARID1A (HR=0.26) and PIK3CA (HR=0.27) metagenes were associated with survival, respectively. Overall, using the combined metagene the majority of the significant mutated genes retained their prognostic power. Mutations of specific genes impacted their own expression and prognosis. The expression of TP53 (AUC=0.609, p=2.60E-06), and MAP3K1 (AUC=0.617, p=6.07E-03) was higher in samples with a mutation while the expression of CDH1 (AUC=0.684, p=2.72E-07), PTEN (AUC=0.687, p=1.47E-04), and BRCA1 (AUC=0.608, p=2.24E-02) was lower. Conclusions: Our finding support that specific mutated genes may differentially impact prognosis in breast cancer subtypes. Further efforts are required to understand the biological and prognostic role of specific activating and inactivating mutations across molecular breast cancer subtypes. Citation Format: Gyorffy B, Pongor L, Szabo A, Bottai G, Pusztai L, Santarpia L. Somatic mutation patterns differentially affect survival in breast cancer molecular subtypes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD6-06.