Department of Breast Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, NO.160 Pujian Road, Shanghai, 200127, China.
Department of Gynaecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
BMC Med Genomics. 2023 Oct 27;16(1):267. doi: 10.1186/s12920-023-01685-7.
Our previous study illustrated the predictive value of serum gamma-glutamyl transpeptidase (GGT) for neoadjuvant chemotherapy (NAC) sensitivity in breast cancer patients. In this study we aim to determine whether single nucleotide polymorphisms (SNPs) in the gamma-glutamyltransferase 1 (GGT1) gene are related to the NAC response and adverse events and to find out a genetic marker in predicting NAC sensitivity.
Three SNP loci (rs8135987, rs5751901, rs2017869) of GGT1 gene were selected and tested among breast cancer patients reciving NAC. Four genotype models were used in SNP analysis: co-dominant model compared AA vs. Aa vs. aa; dominant model compared AA vs. Aa + aa; recessive model compared AA + Aa vs. aa; over-dominant model compared AA + aa vs. Aa. Chi-squared test and multivariable logistic regression analysis were performed between SNP genotypes, haplotypes and pathological complete response(pCR), adverse events as well as serum GGT level.
A total of 143 patients were included in the study. For SNP rs8135987 (T > C), the TC genotype in over-dominant model was inversely related with pCR (adjusted OR = 0.30, 95% CI 0.10-0.88, p = 0.029) as well as the risk of peripheral neuropathy (adjusted OR = 0.39, 95% CI 0.15-0.96, p = 0.042). The TC genotype in dominant model was significantly associated with elevated serum GGT level (OR = 3.11, 95% CI 1.07-9.02, p = 0.036). For rs2017869 (G > C), the occurrence of grade 2 or greater neutropenia (OR = 0.39, 95% CI 0.08-0.84, p = 0.025) and leukopenia (OR = 0.24, 95% CI 0.08-0.78, p = 0.017) were both significantly reduced in patients with CC genotypes. For rs5751901(T > C), the CC genotype could significantly reduce the risk of grade 2 or greater neutropenia (OR = 0.29, 95% CI 0.09-0.96, p = 0.036) and leukopenia (OR = 0.27, 95% CI 0.09-0.84, p = 0.024) in recessive model.
The GGT1 gene SNPs might be an independent risk factor for poor response of NAC in breast cancer patients, providng theoretical basis for further precision therapy.
我们之前的研究表明血清γ-谷氨酰转肽酶（GGT）对乳腺癌患者新辅助化疗（NAC）敏感性的预测价值。在这项研究中，我们旨在确定 γ-谷氨酰转移酶 1（GGT1）基因中的单核苷酸多态性（SNP）是否与 NAC 反应和不良事件相关，并找到预测 NAC 敏感性的遗传标志物。
选择 GGT1 基因中的三个 SNP 位点（rs8135987、rs5751901、rs2017869）并在接受 NAC 的乳腺癌患者中进行检测。在 SNP 分析中使用了四种基因型模型：共显性模型比较 AA 与 Aa 与 aa；显性模型比较 AA 与 Aa+aa；隐性模型比较 AA+Aa 与 aa；超显性模型比较 AA+aa 与 Aa。卡方检验和多变量逻辑回归分析用于 SNP 基因型、单倍型与病理完全缓解（pCR）、不良事件以及血清 GGT 水平之间的关系。
共有 143 名患者纳入研究。对于 SNP rs8135987（T>C），超显性模型中的 TC 基因型与 pCR（调整后的 OR=0.30，95%CI 0.10-0.88，p=0.029）以及周围神经病变的风险呈负相关（调整后的 OR=0.39，95%CI 0.15-0.96，p=0.042）。显性模型中的 TC 基因型与血清 GGT 水平升高显著相关（OR=3.11，95%CI 1.07-9.02，p=0.036）。对于 rs2017869（G>C），CC 基因型患者发生 2 级或更高级别的中性粒细胞减少症（OR=0.39，95%CI 0.08-0.84，p=0.025）和白细胞减少症（OR=0.24，95%CI 0.08-0.78，p=0.017）的风险显著降低。对于 rs5751901（T>C），CC 基因型可显著降低 2 级或更高级别的中性粒细胞减少症（OR=0.29，95%CI 0.09-0.96，p=0.036）和白细胞减少症（OR=0.27，95%CI 0.09-0.84，p=0.024）的风险在隐性模型中。
GGT1 基因 SNP 可能是乳腺癌患者 NAC 反应不良的独立危险因素，为进一步精准治疗提供了理论依据。
