Abstract P3-08-07: Expression of the novel tumor suppressor gene SAMHD1 correlates with favourable clinical outcome in basal-like (BL) early breast cancer

Abstract

Abstract Introduction: The SAM domain and HD domain 1 (SAMHD1) protein is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase initially described to restrict human immunodeficiency virus type 1 (HIV-1) in the immune cells through depletion of intracellular dNTP substrates required for HIV-1 replication. Because of its ability to deplete the dNTP pool, SAMHD1 may operate as a tumor suppressor in cancer. Mutations of SAMHD1 gene have been associated with Aicardi-Goutières syndrome and have been detected in certain hematologic malignancies. However, the potential role of SAMHD1 in breast oncogenesis as well as its expression patterns and clinical significance are not yet known. Methods: SAMHD1 expression was investigated at the mRNA and protein levels in a large cohort consisting of 562 patients diagnosed with primary breast cancer between 1997-2005 in Stockholm health care region. Gene expression profiling was performed using DNA microarrays (GSE48091). SAMHD1 protein expression was assessed by a previously validated double immunostaining method (SAMHD1/CD68) using tissue microarrays (TMA) that included duplicate cores from each tumor and specific antibody (SAMHD1, Bethyl laboratories; #A303-691A). CD68+ macrophages known to be strongly positive for SAMHD1 served as positive controls in each tumor core. Any nuclear staining for SAMHD1 was considered positive with either weak (1), intermediate (2), or strong (3) staining intensity. At least 500 neoplastic cells were counted in order to determine the percentage of SAMHD1+ tumor cells. The latter was combined with the staining intensity into the quickscore method, and a positive cutoff of greater or equal to 3 was used to dichotomize SAMHD1 protein expression. Survival analyses were performed using the Kaplan-Meier method (SAMHD1 mRNA level cutoff: median) and Cox proportional hazards models (univariate and multivariable analysis; SAMHD1 mRNA level was evaluated as continuous variable). Distant metastasis-free survival (DMFS) was used as the clinical endpoint. Results: Evaluable immunohistochemical (IHC) data for SAMHD1 were available for 439 of 562 (78%) patients. In the entire study group, SAMHD1 mRNA and protein levels were significantly correlated (Mann-Whitney p=5.2e-5). SAMHD1 mRNA level was higher in HER2-enriched (PAM50) tumors compared to the other subtypes (Kruskal-Wallis p=2.5e-12). By IHC, SAMHD1 was positive in 33/192 (17%) Luminal A, 17/85 (20%) Luminal B, 10/49 (20%) HER2-enriched, and 26/99 (26%) basal-like (BL). In the entire cohort, SAMHD1 expression was not associated with DMFS. However, in the group of BL subtype (n=122), high SAMHD1 mRNA level (logrank p=0.026) or SAMHD1 protein expression (logrank p=0.025) were associated with favourable DMFS. Using the Cox proportional hazards model, high SAMHD1 mRNA level (HR=0.68; 95% CI=0.48-0.96; p=0.029) and high SAMHD1 protein expression (HR=0.22; 95% CI=0.05-0.95; p=0.042; reference: SAMHD1 negative) were associated with improved survival in patients with BL subtype of breast cancer. In the multivariable analysis, SAMHD1 mRNA level was independently associated with survival (HR=0.66; 95% CI=0.47-0.94; p=0.021), after adjustment for lymph node status and tumor size, along with lymph node status (HR: 3.29; 95% CI=1.58-6.83; p=0.001; reference: lymph node negative) in the BL subgroup. At the meeting we will also present data on prognosis in relation to given adjuvant therapies.Conclusions: SAMHD1 gene is differentially expressed at the mRNA and protein levels among the breast cancer subtypes. SAMHD1 expression is significantly and independently associated with favourable clinical outcomes in breast cancer of BL subtype. Citation Format: Maria Kouvaraki, Emmanuil G Sifakis, Ioannis Zerdes, Nikolas Herold, Jonas Bergh, George Z. Rassidakis, Theodoros Foukakis. Expression of the novel tumor suppressor gene SAMHD1 correlates with favourable clinical outcome in basal-like (BL) early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-07.