Abstract P2-17-02: SMC6 down-regulation: marker of genetic instability and poor outcome in breast cancer

Abstract Genetic instability commonly found in tumors may be a consequence of imbalance in homologous recombination (HR), a mechanism of DNA double-strand break (DSB) repair dependent on the formation and resolution of Holliday junctions’ structures for genomic stability maintenance. The SMC6 is involved in DSB repair. The SMC6 gene is structurally located very close to the GEN1 gene in a head-to-head organization sharing a bi-directional promoter, and the encoded protein is also involved in HR. Herein, we explored the association between SMC6 expression, genomic instability, and prognosis of breast cancer (BC). SMC6 and GEN1 expression and Copy Number Variation (CNV) data measured by qRT-PCR and CGH array, respectively, were assessed in 33 BC of women non-carrier BRCA1/BRCA2-mutations. The SMC6 protein expression was evaluated on a Tissue Microarray containing 74 BC samples classified as low (negative/weak) or high (moderate/strong) according to SMC6 nuclear staining. SMC6 and GEN1 expressions were directly correlated (p=0.821). Moreover, SMC6-low tumors tend to show higher CNV. Yet, the SMC6-low group presented poorer disease-free survival (DFS) than the SMC6 high group (log-rank=0.008). Further, SMC6 expression broke the DFS ER+ cohort in groups of distinct prognoses (log-rank=0.029). By in silico data analysis, SMC6 downregulation was also associated with worse prognosis in some BC subtypes. Our findings point to a possible association between SMC6 down-regulation and BC poor outcomes, suggesting that SMC6 may serve as an indicator of tumor genetic instability for BC patients. Supported by Fapesp and CNPq. Citation Format: Flavia R. Rotea Mangone, Ana Cristina V. Krepischi, Dirce M. Carraro, Maria A. Nagai. SMC6 down-regulation: marker of genetic instability and poor outcome in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-17-02.