Abstract 3370: Comparative analyses of multi-omics profiles reveal distinctive molecular signatures of young Asian breast cancers
Authors: Park Yeon Hee , Ding Ying , Lee Soo-Hyeon , Jung Hae Hyun , Chung Woosung , Cho Soonweng , Kim Jin-Ho , Deng Shibing , Choi Yoon-la , Fernandez Julio , Lee Se Kyung , Kim Seok Won , Lee Jeong Eon , Kim Ji-Yeon , Ahn Jin Seok , Im Young-Hyuck , Nam Seok Jin , Park Woong-Yang , Kan Zhengyan 
Published: July 2017

Abstract
Breast cancers (BC) in younger, premenopausal patients (YBC) tend to be more aggressive with worse prognosis, higher chance of relapse and poorer response to endocrine therapies compared to breast cancers in older patients. The proportion of YBC (age ≤ 40) among BC in East Asia is estimated to be 16-32%, significantly higher than the 7% reported in Western countries. In addition, approximately half of the Asian BC patients were premenopausal compared to 15-30% in the West. To characterize the molecular bases of Asian YBC, we have performed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) on tumor and matched normal samples from 168 Korean BC patients consisting of 106 YBC cases (age ≤ 40) and 62 OBC cases (age &gt; 40). We then performed comparison analyses with the TCGA BC cohort consisting of 1,116 tumors from primarily Caucasian patients, also grouped by age into YBC (age ≤ 40), IBC (40 &lt; age ≤ 60) and OBC (age &gt; 60). We performed logistic regression analyses to identify differentially expressed (DE) genes and pathways among age-based cohorts while controlling for the confounding effects of molecular subtype, tumor purity and stage. Within the Asian cohort, we found that estrogen response, endocrine therapy resistance, and various metabolism pathways are up-regulated in YBCs while cell cycle, proliferation and inflammatory pathways are up-regulated in OBCs. To separately examine molecular signatures from tumor, stroma and normal compartments, we used non-negative matrix factorization (NMF) analyses to virtually dissect bulk tumor expression data and identified 14 factors including 3 factors associated with normal tissues, 1 factor associated with stroma and 1 factor associated with tumor infiltrating leukocytes (TILs). By examining the correlation between pathway gene expression and NMF factors, we inferred that DE pathways such as fatty acid metabolism, bile acid biosynthesis, and epithelial-to-mesenchymal transition (EMT) were mainly active in stromal and normal tissue compartments. The TIL factor was significantly enriched in Asian BCs relative to Caucasian BCs with the highest TIL factor weight observed in Asian OBCs. Using gene expression signatures representing distinct types of TILs, we classified the combined cohort into three subtypes of varying TIL activities. Consistent with results from the NMF analysis, the TIL-high subtype is also significantly enriched in Asian BCs relative to Caucasian BCs. To our knowledge, this is the first large-scale multi-omics study of Asian breast cancer. Comparative analyses of multi-omics profiles from Asian and primarily Caucasian BC cohorts identified distinguishing molecular signatures associated with Asian BCs. Further, many signatures appeared to be specific to non-tumor compartments within bulk tumor, indicating that young Asian BCs may harbor distinctive tumor microenvironment.
Citation Format: Yeon Hee Park, Ying Ding, Soo-Hyeon Lee, Hae Hyun Jung, Woosung Chung, Soonweng Cho, Jin-Ho Kim, Shibing Deng, Yoon-la Choi, Julio Fernandez, Se Kyung Lee, Seok Won Kim, Jeong Eon Lee, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Seok Jin Nam, Woong-Yang Park, Zhengyan Kan. Comparative analyses of multi-omics profiles reveal distinctive molecular signatures of young Asian breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3370. doi:10.1158/1538-7445.AM2017-3370