Gene-54. Investigating the Roles of Ncor1 and Ncor2 in Metastatic Invasion Into the Spine

Abstract

Anywhere from 30–70% of osseous metastatic disease occurs in the spine across many different tumor types. These metastases lead to debilitating pain and neurologic dysfunction significantly reducing patients’ quality of life. Unfortunately, the cause of preferential metastatic growth to the spine is not understood. The purpose of this study was to identify the role of NCOR1 and NCOR2/SMRT, genes included in Cancer Gene Census (https://cancer.sanger.ac.uk/cosmic), in the promotion of metastatic spread to the spine. NCOR1, located on chromosome 17, and NCOR2, located on chromosome 12, encode for proteins that mediate ligand-independent transcription repression by forming a complex that activates HDAC3. Studies have shown that low expression of NCOR1 and NCOR2 is associated with decreased median survival in some cancers. Our lab collected tumors and blood/bone marrow samples from 9 patients with different primary tumors that metastasized to the spine, and sequenced their DNA. Based on preliminary bioinformatics analysis, we discovered a substitution of thymine to cytosine at chr17:16165160 in the NCOR1 sequence, which results in a nonsense mutation that ends transcription in the second exon. After Sanger sequencing validation, this mutation was found to be present in both the tumor and control samples of all patients, resulting in two possible interpretations: a germline mutation of NCOR1 sequence or the presence of tumors cells in the blood. In addition, by bioinformatics analysis, we identified a substitution of cytosine to thymine at chr12:124341916 in exon 34 of the NCOR2 sequence, resulting in a missense mutation that changes an alanine to threonine. Further experimentation must be done to determine the role of NCOR1 and NCOR2 in metastatic spread to the spine. The hope is to identify targetable molecules and pathways for the design of novel therapies aimed to improve the outcome of these patients.