Abstract LB-380: Alcohol consumption and transcriptomic differences in breast tumor

Abstract

Abstract Objective: Alcohol consumption is consistently positively associated with breast cancer risk in epidemiologic studies and the association generally appears stronger among estrogen receptor (ER) positive tumors. However, the underlying biologic mechanism is not completely understood. Methods: We evaluated pre-diagnostic alcohol intake in relation to transcriptome profiles of invasive breast cancers diagnosed 1990-2009 in the Nurses’ Health Studies using a custom Affymetrix Human Transcriptome array. RNA was extracted from formalin fixed paraffin embedded breast tumor and tumor adjacent normal tissue. Cumulative average and recent alcohol intake were used in the analysis (defined as categorical: 0, >0 - <10, 10+ g/d or continuous: per 10 g/d). Multivariable linear regression was used to identify differentially expressed genes in tumor (n = 602) and adjacent normal (n = 508) samples, respectively. We further conducted gene set enrichment analysis (GSEA) to assess biological pathways. Differentially expressed genes or gene sets were considered statistically significant if false discovery rate < 0.1. Results: When comparing cumulative average or recent alcohol intake 10+ g/d vs. 0, no significantly differentially expressed genes were identified in all tumors combined or in stratified analyses by ER or human epidermal growth factor receptor 2(HER2) status. However, when recent alcohol assessed as per 10 g/d, SUSD2 was significantly up-regulated and GTPBP6 significantly down-regulated in HER2+ and ER- tumors, respectively. No genes were significantly differentially expressed according to alcohol intake in tumor adjacent normal tissue. When evaluating recent alcohol intake 10+ g/d vs 0, differentially expressed gene sets identified through GSEA suggest that translation, cell cycle, and response to DNA damage and DNA repair were up-regulated while lipid metabolism and signaling and retinol metabolism were down-regulated in ER+ tumors; in ER- tumors, immune function/inflammatory response was up-regulated in addition to the up-regulation of genes involved in translation and cell-cycle. We further verified these gene sets (n = 32 and 4 up- and down- regulated, respectively in ER+ tumors; n = 89 and 2 up- and down-, respectively in ER- tumors) in The Cancer Genome Atlas data set. However, such differentially expressed gene sets were not observed in the analysis of cumulative average alcohol. In tumor adjacent normal samples, in addition to the down-regulation in lipid metabolism and signaling (consistent with ER+ tumors), alcohol metabolism (particularly in mitochondria), DNA damage response and apoptosis were significantly down-regulated (contrary to ER+ tumors), when comparing recent alcohol 10+ g/d vs. 0. Conclusion: To the best of our knowledge, this is the first study to evaluate pre-diagnostic alcohol consumption and breast tumor transcriptomic profiles. Assessment of transcriptomic differences with alcohol intake in tumor and/or adjacent normal tissue may help provide insights into the biologic mechanism underlying the alcohol and breast cancer association. Citation Format: Jun Wang, Yujing J. Heng, Aditi Hazra, A. Heather Eliassen, Rulla Tamimi, David Hunter, Andrew Beck, Susan Hankinson. Alcohol consumption and transcriptomic differences in breast tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-380.