Belyavskaya Valentina A, Prudnikova Tatiana Y, Domanitskaya Natalya V, Litviakov Nikolay V, Maksimov Vladimir N, Cherdyntseva Nadezhda V, Grigorieva Elvira V
Research Center of Virology and Biotechnology, Vector, Koltsovo 630559, Novosibirsk region, Russia.
Institute of Molecular Biology and Biophysics, 630117 Novosibirsk, Russia.
Gene. 2017 Sep 10;628:224-229. doi: 10.1016/j.gene.2017.07.054. Epub 2017 Jul 20.
d-Glucuronyl C5-epimerase (GLCE) is one of key enzymes in heparan sulfate biosynthesis and possesses tumour-suppressor function in breast carcinogenesis. Here, we investigated a potential involvement of GLCE polymorphism(s) in breast cancer development in Siberian women population. Comprehensive analysis of SNP databases revealed GLCE rs3865014 (Val597Ile) missense polymorphism as the main significantly present in human populations. According the TaqMan-based SNP assay, allele distributions for the rs3865014 (A>G) were similar in healthy Siberian women (n=136) and cancer patients (n=129) (A0,73:G0,27) and intermediate between the European and Asian populations, while genotype distributions were different, with the increase of AG rate in breast cancer patients (OR=1.76; 95% CI=1.04-1.90; P(Y)=0.035 χ=4.44). Heterozygous AG genotype was associated with tumour size (OR=3.67, P(Y)=0.004), ER-negative tumours (OR=3.25, P(Y)=0.0028), triple-negative tumours (OR=4.94, P(Y)=0.015) but not menopausal status, PR and HER-2 status, local or distant metastasis. Homozygous GLCE genotypes (AA/GG) were more common for ER+PR+ luminal A breast cancer (OR=0.25, P(Y)=0.031). Loss-of-heterozigosity was identified in 5 of 51 breast tumours and the loss of G allele was associated with the decreased GLCE expression. Epidemiologic data for the GLCE SNP in different racial/ethnic groups demonstrated high AG genotype rates as a risk factor not for breast cancer incidence but for poor prognosis of the disease. The obtained data suggest an involvement of GLCE rs3865014 in breast cancer development. Heterozygous AG genotype might be a risk factor for breast cancer susceptibility in Siberian women and is associated with aggressive ER-negative and triple-negative cancer subtypes.
d-葡萄糖醛酸C5-表异构酶（GLCE）是硫酸乙酰肝素生物合成中的关键酶之一，在乳腺癌发生过程中具有肿瘤抑制功能。在此，我们研究了GLCE基因多态性在西伯利亚女性人群乳腺癌发展中的潜在作用。对单核苷酸多态性（SNP）数据库的综合分析显示，GLCE rs3865014（Val597Ile）错义多态性是人类群体中主要显著存在的多态性。根据基于TaqMan的SNP检测，rs3865014（A>G）的等位基因分布在健康的西伯利亚女性（n = 136）和癌症患者（n = 129）中相似（A 0.73:G 0.27），且介于欧洲和亚洲人群之间，而基因型分布不同，乳腺癌患者中AG率增加（比值比[OR]=1.76；95%置信区间[CI]=1.04 - 1.90；P(Y)=0.035，χ=4.44）。杂合AG基因型与肿瘤大小（OR = 3.67，P(Y)=0.004）、雌激素受体（ER）阴性肿瘤（OR = 3.25，P(Y)=0.0028）、三阴性肿瘤（OR = 4.94，P(Y)=0.015）相关，但与绝经状态、孕激素受体（PR）和人表皮生长因子受体2（HER-2）状态、局部或远处转移无关。纯合GLCE基因型（AA/GG）在ER+PR+管腔A型乳腺癌中更为常见（OR = 0.25，P(Y)=0.031）。在51个乳腺肿瘤中有5个检测到杂合性缺失，G等位基因的缺失与GLCE表达降低相关。不同种族/民族群体中GLCE SNP的流行病学数据表明，高AG基因型率不是乳腺癌发病率的危险因素，而是该疾病预后不良的危险因素。所获数据表明GLCE rs3865014参与了乳腺癌的发展。杂合AG基因型可能是西伯利亚女性乳腺癌易感性的危险因素，且与侵袭性ER阴性和三阴性癌症亚型相关。
