Potential role of SMC6 downregulation as an indicator of tumor genetic instability in breast cancer.

Genetic instability is a common feature of cancer. Homologous recombination (HR) is involved in one of the major mechanisms of DNA double strand break repair (DSB) and depends on the formation of Holliday junctions (HJ) that should be solved for the maintenance of genomic stability. Deregulation of HR control mechanisms results in DNA damage. Data from the literature has shown that SMC6 complexed with SMC5 is involved in DSB repair. Previous sequencing data from our group showed the occurrence of some SMC6 genetic variants in sporadic breast cancer. In the present study, we sought to investigate a possible association between SMC6 expression level and genomic instability in breast cancer. SMC6 mRNA expression pattern determined by qRT-PCR and Copy Number Variation (CNV) data obtained by using whole-genome comparative genomic hybridization on microarrays, were determined in a cohort of 33 breast cancer samples of women who did not carry BRCA1/BRCA2 mutations. SMC6 protein expression was carried out in a tissue micro-array containing breast cancers samples. Statistical analyses were performed by using SPSS Software 20. Data comparison revealed that tumors with higher SMC6 mRNA expression showed a trend toward lower median numbers of total CNVs per genome, corroborating the role of SMC6 genomic stability maintenance. SMC6 protein expression was tested in a panel of 74 breast cancer tumors, and cases were classified into two groups: SMC6 negative (negative to weak nuclear staining) and SMC6 positive (moderate to strong nuclear staining). No association among SMC6 staining and clinic-pathologic features was observed. However, patients with SMC6 negative tumors had a trend to a shorter disease-free survival (DFS) and overall survival (OS) than those with SMC6 positive tumors (median DFS 29.0 vs. 172.0 months, Log Rank = 0.123 and median OS 30.47 vs. 153.30 months, Log Rank = 0.117). Although preliminary, our findings point to a possible association between SMC6 downregulation and poor outcome of patients, suggesting theatSMC6 may serve as an indicator of tumor genetic instability for patients with breast cancer. Supported by Fapesp and CNPq. Citation Format: Flavia Rotea Mangone, Ana Cristina Victorino Krepischi, Suely Nonogaki, Dirce Maria Carraro, Maria Aparecida Nagai. Potential role of SMC6 downregulation as an indicator of tumor genetic instability in breast cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A02.