Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics

// Aliccia Bollig-Fischer 1, 5 , Sharon K. Michelhaugh 2, 5 , Priyanga Wijesinghe 1, 5 , Greg Dyson 1, 5 , Adele Kruger 3 , Nallasivam Palanisamy 6 , Lydia Choi 1, 5 , Baraa Alosh 4 , Rouba Ali-Fehmi 4, 5 , Sandeep Mittal 1, 2, 5 1 Department of Oncology, Wayne State University, Detroit, Michigan, USA 2 Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA 3 Department of Obstetrics/Gynecology, Wayne State University, Detroit, Michigan, USA 4 Department of Pathology, Wayne State University, Detroit, Michigan, USA 5 Karmanos Cancer Institute, Detroit, Michigan, USA 6 Henry Ford Health System, Detroit, Michigan, USA Correspondence to: Aliccia Bollig-Fischer, e-mail: bollig@karmanos.org Keywords: breast cancer, brain metastases, copy number variation, oncogenes, targeted therapy Received: March 12, 2015 Accepted: April 11, 2015 Published: April 24, 2015 ABSTRACT Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2 , PIK3CA , NTRK1 , GNAS , CTNNB1 , and FGFR1 . For a subset of the metastatic brain tumor samples ( n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.