Abstract 2533: The genomic and transcriptomic landscape of left versus right sided breast cancer in 410 cases

Background: Studies have shown that unilateral breast cancer is more common on the left (L) than right (R) and that the L breast is often larger than the R. No clear explanation for this finding has been described in the literature. Hypotheses range from complex genomic effects to environmental, hormonal, and anatomical causes. Methods: We performed a retrospective analysis of data from the NantHealth database of 410 commercial cases where WGS (35x germline, 75x somatic) or WES (∼150x). Primary and metastatic breast tumors were included in the analysis. Of these 410 cases, 39.3% were R, 38.5% were L, and 22% were unspecified. Bases adjacent to variant sites were used to determine genomic context (i.e. mutation signatures) as previously reported. Additionally, paired deep whole transcriptomic sequencing (RNA-Seq; ∼200x106 reads per tumor) was performed on 376 of the 410 cases. Nant Breast Cancer Intrinsic Subtypes sorting based on RNAseq assay classified breast tumors into 4 subtypes (LumA/B, Basal-like, and HER2-enriched). Results: Luminal A subtype was significantly overrepresented in R v L (OR=0.53, p=0.015). Similarly, R-side cases were significantly enriched for estrogen response gene expression by GSEA. However, only slight differential expression of ESR1 and MKI67 was observed specifically in individuals between 40 and 50 years old. Germline variants in the following genes were associated with sidedness: MEN1, KIT, JAK2, TET2, EP300, MET, FLCN, and KMT2D, and somatic variants within the following genes were associated with sidedness: CACNA1E, AGRN, RIMS2, TTYH3, KRTAP10-6, and DDX60L. However, significance of the variant frequency differences was lost after multiple-hypothesis correction. No significant differences between L and R were noted in tumor stage, HER2, ER, PR, somatic CNV, and mutation signatures, including signature 3 (BRCAness). Conclusions: Despite performing WGS/WES a paucity of differentially mutated genes were seen between left and right sided breast tumors. RNAseq analysis reveals that right sided breast cancers may be more likely to involve ESR1-signaling and be Luminal A subtype. Right-sided ESR1-signaling may be especially relevant in perimenopausal cases, however the current cohort is underpowered to achieve significance in this analysis. Citation Format: Yulia Newton, Christopher Szeto, Charles Vaske, Leia Reddy, Sandeep Reddy. The genomic and transcriptomic landscape of left versus right sided breast cancer in 410 cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2533.