ASSOCIATION OF E-SELECTIN S128R POLYMORPHISM WITH HEREDITARY BREAST CARCINOMA SUSCEPTIBILITY IN TURKISH PATIENTS WITHOUT BRCA1/2 GERMLINE MUTATIONS
Yararbas K, Atalay PB
*Corresponding Author: Kanay Yararbas, M.D., Assistant Professor, Department of Medical Genetics, Acibadem Mehmet Ali Aydinlar University Faculty of Medicine; İçerenköy Mahallesi, Kayisdagi Caddesi, No: 32, 34742, Istanbul, Turkey. Tel: +90-216-500-4785. Fax: +90-216-500-5076. E-mail: kanay.yararbas@ acibadem.edu.tr
page: 27

INTRODUCTION

Breast cancer is one of the most common invasive cancers in the female population worldwide and in Turkey [1]. Breast cancer is a multifactorial disease driven by both genetic and non genetic etiological factors. Non genetic environmental factors such as pregnancy, hormone replacement therapies, obesity and alcohol consumption are known to be closely linked to breast cancer risk [2]. The well-characterized hereditary form of breast cancer is caused by germline pathogenic variants in BRCA1/2 [3]. Early studies conducted on selected multiple-case families have estimated that approximately 80.0% of BRCA1/2 mutation carriers would develop breast cancer by age 70 [4,5]. However, in a later meta-analysis study that pooled the data of studies including patients unselected for family history, it was reported that the observed risk for breast cancer development in BRCA1 and BRCA2 mutation carriers by age 70 was 65.0 and 45.0%, respectively, which were lower than the estimated value [6,7]. Additionally, individuals of high-risk families who do not carry BRCA1/2 mutations are also at an increased risk for developing breast cancer [4,7]. All these data strongly suggest that other than the well-studied BRCA1/2 genes, additional genetic factors are also involved in a predisposition to breast cancer. However, not much is known about the genes contributing to breast cancer susceptibility in non carriers of the BRCA1/2 mutations. Selectins are adhesion molecules, which are expressed by endothelial cells, thrombocytes and leukocytes, and have three subsets, namely L-, P- and E-selectins [8]. Structurally, selectins contain an N-terminal, calciumdependent lectin domain, an epidermal growth factor-like domain, regulatory elements, a transmembrane domain, and a short cytoplasmic tail [9]. Intracellular and extracellular interactions mediated by adhesion molecules are critical for the dissemination of metastatic tumor cells. Loss of cell-cell and/or cell-matrix adhesions allows malignant tumor cells to escape from their primary micro environment and to acquire a more motile and invasive phenotype, and thereby enables them to migrate to the other sides of the body. Consistent with this, E-selectin is involved in migration and metastasis [8,10-18] that are two critical steps in carcinogenesis. E-selectin is a cell surface glycoprotein expressed on endothelial cells after activation by cytokines. Several studies have demonstrated that serum E-selectin levels are elevated in patients with a variety of cancers, including ovarian, breast and gastric cancers [14]. Numerous single nucleotide polymorphisms (SNPs) of the E-selectin gene have been identified, among which the most common variant is the g.7161A/C or A561C missense variant (rs5361) leading to a serine to arginine substitution in exon 4 at position 128 (S128R) (NG_012124.1:g.7161A>C, NM_000450.2: c.445A>C, NP_000441.2: p.Ser149Arg) [19]. The E-selectin S128R (A/C) polymorphism alters the binding specificity of the extracellular domain and thus facilitates ligand binding, which in turn improves the adhesion of lymphoid and myeloid cells to the endothelium [20-22]. In the E-selectin gene variants, the S128R polymorphism is of particular interest as it is clinically associated with increased cancer risk [23]. The present study aimed to investigate whether the S128R polymorphism of the E-selectin gene contributes to development of breast cancer in patients with breast cancer but without BRCA1/2 mutations in the Turkish population. To the best of our knowledge, this study is the first to investigate the correlation between the S128R polymorphism and breast cancer in the absence of BRCA1/2 mutations in the Turkish population.



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