Abstract LB-217: Genes involved in non-malignant breast phenotypes are widely expressed in multiple cancers and provide novel biomarkers of clinical outcomes and therapeutic response
Authors: Marcia V. Fournier, John C. Obenauer, Andreia Maer, Edward C. Goodwin
Journal: Cancer Research (2018)

Abstract From over two hundred driver mutations identified to date, only about a dozen are FDA-approved biomarkers, and there is an unmet need to discover novel suitable biomarkers. We selected novel biomarkers based on non-malignant breast epithelial cell phenotypes and identified 325 genes (BA325) showing 32 significant oncology drug associations. A total of 251 genes out of 325 are unique and not found in any of 9 other oncology panels investigated, suggesting that BA325 may yield novel insights regarding tumor biology, clinical outcomes, and novel therapeutic targets, not covered by current tools. While prior work has validated the utility of BA325 in breast cancer, the current study investigates BA325 expression in other tumor types beyond breast. We tested BA325 expression in 8 tumor types (breast, colon, lung, ovarian, prostate, pancreatic, gastric cancers, and leukemia), using two independent public data sets for each, totaling 3,563 samples in 16 datasets. All used Affymetrix HG-U133A or Plus 2.0 microarrays. Samples were normalized within each study using RMA and batch-corrected across studies. BA325 expression levels were investigated, showing at least 324 of the 325 genes expressed above background levels (log2 &amp;gt; 4) in all cases tested. The expression profile of BA325 differed in magnitude and pattern across tumor types from 1,000 randomly generated sets of 325 genes. Surprisingly, 102 of the BA325 genes were among 3,804 published housekeeping (HK) genes, with 7 of them present in a predictive signature developed for breast cancer chemotherapy response. The results suggest HK genes may play a role in the underlying biology of how cancer cells respond to treatments. A set of 119 genes showed tissue-specific expression (10 breast, 2 colon, 7 lung, 3 ovarian, and 42 prostate), while 87 genes showed the least variation across tumors (4-fold change or less), including the genes MPRIP, MUS81, and AKT1. Twenty seven (27) of the tissue-specific genes and 48 of the least-varying genes are also reported to be HK genes. Differential expression was tested by unsupervised clustering in 14 of the 16 studies. BA325 genes successfully distinguished tumor and normal samples in gastric and ovarian cancers, and subtypes of lung and breast cancers, with implications for treatment responses. We conclude that BA325 expression profiles in all datasets examined include both tissue-specific genes and genes with similar expression across tissues. Preliminary results indicate BA325 genes may have utility as biomarkers in a surprisingly wide variety of tumor types (including leukemia) in addition to breast cancer, with discriminatory power in at least gastric, ovarian, lung and breast cancers. Thus, BA325 can greatly increase the biomarker repertoire beyond oncogenes or other driver genes and may provide relevant insight in novel oncology therapeutic targets. Citation Format: Marcia V. Fournier, John C. Obenauer, Andreia Maer, Edward C. Goodwin. Genes involved in non-malignant breast phenotypes are widely expressed in multiple cancers and provide novel biomarkers of clinical outcomes and therapeutic response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-217.