Comprehensive characterization of neurotransmitters and neuronal signaling gene alterations in invasive breast cancers

Abstract BACKGROUNDIt has been reported that the sympathetic nervous system and associated neurotransmitters (NTs) play a pivotal role in driving breast cancer (BC) tumorigenesis and metastasis, however, comprehensive characterization of these pathways in BC is lacking. The purpose of this study was to retrospectively characterize NTs and neuronal signaling (NTNS) gene alterations in a large real-world BC cohort. METHODS A total of 6464 BC tumors were analyzed by next generation sequencing (NextSeq, 592 genes and WES, NovaSEQ, 720 genes) and whole transcriptome sequencing (WTS, NovaSeq) at Caris Life Sciences. Gene set variation analysis (GSVA) scores were calculated (positive: higher gene expressions in a selected gene set compared to genes outside that gene set in each tumor specimen, vice versa for negative) to assess expression of major NTNS genes, including GABA, nicotinic (NIC), muscarinic (MUS), dopamine (DA), reelin (RELN), and glial cell line-derived neurotrophic factor (GDNF). GSVA scores were compared by histologic subtype, primary or metastatic site, and hormone receptor (HR) and HER2 status with corrected Wilcoxon-Mann-Whitney testing. All significance levels were p<0.01. RESULTS The 6464 BC specimens in this cohort included 2520 primary sites and 3944 metastasis (mets) (liver: 1012; lymph node: 714; bone: 575; lung: 420; brain: 196). Predictive biomarker status in this cohort was HR+/HER2-: 3705; HR+/HER2+: 238; HR-/HER2+: 189; TNBC: 1654. Invasive ductal carcinomas (IDC) were the most common histologic subtype and demonstrated significantly higher GSVA scores for RELN and NIC pathways with respect to invasive lobular carcinomas (ILC) (Table). TNBC tumors had significantly higher enrichment overall (GABA, -0.04 vs -0.14; RELN, -0.05 vs -0.31; DA, -0.03 vs -0.08; MUS, 0.13 vs -0.16; NIC, 0.01 vs -0.12; and GDNF, 0.04 vs -0.04). HR-/HER2+ had significantly higher scores in GABA, -0.04 vs -0.14; RELN, -0.03 vs -0.31; MUS, 0.12 vs -0.16; and NIC, -0.01 vs -0.12 genes. Brain mets had significantly enriched pathway scores for GABA, 0.30 vs -0.13; MUS, 0.15 vs -0.08; and NIC, 0.13 vs -0.09 compared to primary tumors. Similarly, GABA,0.09 vs -0.13; DA, 0.07 vs -0.05; MUS, 0.17 vs -0.08; and NIC, 0.02 vs -0.09 pathways were enriched in bone mets compared to those from primary tumors. CONCLUSION Our results demonstrate that NTNS pathways are significantly enriched in IDC, TNBC tumors, and particularly in brain and bone mets. Our data advance the current understanding of the role of NTNS pathways in BC tumorigenesis and metastasis. Further investigation on genetic. determinants and signaling alternations associated with the observed NTNS pathway deregulation is warranted and could inform the development of novel therapeutic strategies. Significant comparisons with Bonferroni corrected p values are shown with an asterisk. Citation Format: Irene Kang, Krutika Deshpande, Sarah Persing, Jun Yin, Joanne Xiu, Wolfgang Michael Korn, Jia Zeng, Evanthia T Roussos-Torres, Janice Lu, Darcy Spicer, Stephen F Sener, Antoinette R Tan, Ashley Sumrall, David SB Hoon, Cynthia X Ma, Carey K Anders, Heather L McArthur, Reva Basho, Heinz-Josef Lenz, Josh Neman. Comprehensive characterization of neurotransmitters and neuronal signaling gene alterations in invasive breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD6-06.