Identification and characterization of three Siglec15-related immune and prognostic subtypes of breast-invasive cancer

Abstract

Sialic acid-binding immunoglobulin-like lectin 15 (Siglec15) is an immune checkpoint molecule that can inhibit T cell proliferation and have anti-tumor immunity. We explored the correlation between Siglct15 and the clinical features, mutation frequency, and prognosis of breast cancer. 122 upregulated and 11 downregulated genes between Siglet15-high and -low expression groups of 1109 breast invasive cancer samples (BRCA) obtained from the Cancer Genome Atlas (TCGA) were identified. Three subtypes (C1-C3) of BRCA based on Siglec15 were identified from TCGA datasets via consensus cluster plus analysis. The clinical characteristics, functional enrichments, immune environment, mutation frequency, prognosis were compared among these subgroups and were verified using GSE20685 and GSE31448 cohorts. C3 with highest level of Siglec15 expression was correlated with early tumor stage, hormone receptor-positive tumors, luminal A molecular subtype, lowest tumor mutational burden (TMB) score, lowest programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) expression, upregulated PI3K-Akt pathway and advantage of prognosis. C2 with lowest level of Siglec15 was associated with advanced stage, basal-like subtype, highest TMB score, highest PD-1 and PD-L1 expression, upregulated p53 signaling pathway and worse prognosis. Univariate and multivariate Cox regression analysis demonstrated that Siglec15-related subtype was an independent prognostic factor for breast cancer patients. Siglec15 related immunotherapy may be an important candidate for breast cancer patients especially for luminal subtype, independently of blockade of PD-1/PD-L1 immunotherapy. In conclusion, we identified three Siglec15-related subtypes of BRCA, helping us to understand the immunological function and significance of Siglec15 in the BRCA.