C1236T、G2677T/A和C3435T基因多态性与乳腺癌分子分型的关系及意义

摘要

目的：观察多药耐药基因1（MDR1）第12、21及26外显子C1236T、G2677T/A和C3435T基因多态性在乳腺癌患者外周血中的分布，分析其与分子分型的关系。方法应用高分辨熔解曲线（HRM）技术检测400例乳腺癌患者C1236T、G2677T/A及C3435T基因多态性。采用Hardy-Weinberg遗传平衡检验进行基因型分布遗传平衡吻合度检验。参照2013年St.Gallen国际专家乳腺癌分子分型共识。分析乳腺癌患者中C1236T、G2677T/A和C3435T基因型分布特点，并探讨其与分子分型的关系。结果（1）400例乳腺癌患者中C1236T、G2677T/A和C3435T中分别有2例、3例和2例标本未得出基因分型结果，C1236T位点CC、CT和TT基因型分别占16.08%（64/398）、44.22%（176/398）和39.70%（158/398）；G2677T/A位点GG、GT、GA、TT和AT基因型分别占16.62%（66/397）、44.33%（176/397）、7.05%（28/397）、27.46%（109/397）和4.54%（18/397）；C3435T位点CC、CT和TT基因型分别占21.11%（84/398）、56.03%（223/398）和22.86%（91/398）。经Hardy-Weinberg遗传平衡检验，认为C1236T、G2677T/A和C3435T基因多态性具有群体代表性（P>0.05）。（2）分子分型显示，11例人类表皮生长因子受体2（HER-2，2+）患者未行荧光原位杂交（FISH）检测予以剔除，其中Luminal A型占41.90%（163/389），Luminal B型占32.65%（127/389），HER-2过表达型占13.62%（53/389），三阴型占11.83%（46/389）。（3）C3435T位点CT/TT基因型在Luminal A型患者中的频率高于其在HER-2过表达型和三阴型患者中的频率（χ2=12.011，P=0.001；χ2=13.976，P<0.001），C1236T和G2677T/A基因多态性在不同分子分型中的分布差异无统计学意义（P>0.05）。结论 MDR1基因C3435T位点多态性可以为乳腺癌异质性提供更合理的补充，不同乳腺癌分子分型患者中CT/TT基因表型可能对药物治疗更敏感。%Objective To investigate the distribution of the MDR1 exon12 (C1236T), exon21 (G2677T/A) and exon 26 (C3435T) gene polymorphisms in breast cancer patients, and to analyse their relationship with molecular subtypes of breast cancer. Methods The genotyping of C1236T, G2677T/A and C3435T were detected by polymerase chain reaction (PCR)-high resolution melting (HRM) method in 400 cases of breast cancer. The Hardy-Weinberg equilibrium test was used for ge⁃netic equilibrium distribution of genotype. The molecular subtypes of breast cancer were classified based on St.Gallen Con⁃sensus 2013. The genotype distributions of C1236T, G2677T/A and C3435T in breast cancer were analyzed. Their relation⁃ship with molecular subtypes in breast cancer was analyzed as well. Results ①In 400 cases of breast cancer, there were 2, 3 and 2 specimens did not get genotyping results in C1236T, G2677T/A and C3435T genotype detection. The CC, CT and TT genotypes of C1236T accounted for 16.08% (64/398), 44.22% (176/398) and 39.70% (176/398). GG, GT, GA, TT and AT genotypes of G2677T/A accounted for 16.62%(66/397), 44.33%(176/397), 7.05%(28/397), 27.46%(109/397) and 4.54%(18/397). CC, CT and TT genotypes of C3435T accounted for 21.11%(84/398), 56.03%(223/398) and 22.86%(91/398) re⁃spectively. Hardy-Weinberg genetic equilibrium testing showed that polymorphisms of C1236T, G2677T/A and C3435T had group representation (P<0.05).②Eleven cases of HER-2 (2+) were excluded because they were not verified by FISH de⁃tection when performed molecular subtype of breast cancer. Luminal A subtype accounted for 41.90%(163/389), Luminal B subtype accounted for 32.65%(127/389), HER-2 over-expression subtype accounted for 13.62%(53/389) and triple nega⁃tive subtype accounted for 11.83%(46/389).③CT/TT genotype frequency of C3435T was significantly higher in breast can⁃cer patients with Luminal A subtype than that in breast cancer patients with HER-2 over-expression subtype and triple neg⁃ative subtype (χ2=12.011, P=0.001;χ2=13.976, P<0.001), while there was no statistical difference in C1236T and G2677T/A gene polymorphism between different molecular subtypes of breast cancer (P>0.05). Conclusion C3435T gene polymor⁃phism can explain more accurately heterogeneity of breast cancer. CT/TT genotype in different molecular subtypes of breast cancer may be more sensitive to drug treatment.