Functional genetic variants within the SIRT2 gene promoter in breast cancer

Breast cancer (BC) is the most common cancer in women worldwide. However, BC etiology remains unclear. Approximately 5%-10% of BC cases are inheritable while the rest are sporadic. Large scale genomic studies have reported the molecular landscape and driver genes of BC, explaining the occurrence and development of only a small portion of BC cases. Low frequency and rare genetic variants with large effects may account for missing heritability in BC cases. SIRT2 is a member of sirtuin family of NAD (+)-dependent class III deacetylases. SIRT2 is involved in mitotic progression, oxidative stress, metabolism, microtubule dynamics, cell migration, apoptosis, and differentiation. Recent evidence has suggested that SIRT2 is involved in tumorigenesis. In this study, SIRT2 gene promoter was analyzed in groups of female BC patients (n = 200) and ethnic-matched controls (n = 184). Two novel heterozygous DNA sequence variants (DSVs) (g.38900839G>C and g.38900478G>A) were identified in two patients with luminal B subtype, but not in the controls. These DSVs significantly decreased the transcriptional activity of the SIRT2 gene promoter (P < 0.01) in BC cell lines (MCF-7 and BT-474 cells). The SNP, g.38900291C>G (rs2053071), which was found in both BC patients and controls with similar frequencies, did not significantly alter the transcriptional activity of the SIRT2 gene promoter. Therefore, the SIRT2 gene promoter DSVs may alter transcriptional activity of SIRT2 gene promoter and change SIRT2 levels, contributing to breast cancer development as a rare risk factor.