Nordgard Silje H, Ritchie Marylyn D, Jensrud Sigrid D, Motsinger Alison A, Alnaes Grethe I G, Lemmon Gordon, Berg Marianne, Geisler Stephanie, Moore Jason H, Lønning Per Eystein, Børresen-Dale Anne-Lise, Kristensen Vessela N
Department of Genetics, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway.
Pharmacogenet Genomics. 2007 Feb;17(2):127-36. doi: 10.1097/FPC.0b013e328011abaa.
Many environmental and genetic factors influence the development of chemoresistance. The goal of this study was to characterize the genetic variation in the ABCB1, GSTM1, GSTT1 and GSTP1 genes, as well as the haplotype structure in the ABCB1 gene.
Variants in these genes were studied in 109 healthy controls and 93 breast cancer cases, both of Caucasian origin. The cases were analyzed in relation to TP53 mutation status and response to doxorubicin. Both single and multiple single nucleotide polymorphism analyses were performed.
Chi-square analyses revealed a significant association between TP53 mutation status and both the GA genotype of ABCB1 exon 11 (Ser400Asn) and the GG genotype of GSTP1 (Ile105Val; P<0.01 and P<0.05, respectively). Multifactor dimensionality reduction showed that carriers of the combined GG genotype for GSTP1 and the GG for ABCB1 exon 11 had the highest chance of acquiring a mutation in the TP53 gene (P<0.02). Haplotype analysis of ABCB1 revealed a significantly different distribution of haplotypes between the breast cancer cases and the controls (P<0.01). A specific haplotype association to TP53 mutation (P<0.01) distant metastases (P<0.05) and estrogen receptor status (P<0.05) was also observed in the case group.
An association between polymorphisms in GSTP1 and ABCB1 and risk of acquiring intratumoral TP53 mutations suggests the existence of putative predisposing genotype backgrounds. The degree of linkage disequilibrium in the ABCB1 gene was higher in healthy individuals, whereas haplotypes in the cases seemed degenerated by a number of low frequency variants. This observation may either point to the existence of a protective haplotype in the controls or may underline the importance of the accumulation of low frequency variants as susceptibility factors.
许多环境和遗传因素会影响化疗耐药性的发展。本研究的目的是对ABCB1、GSTM1、GSTT1和GSTP1基因的遗传变异以及ABCB1基因的单倍型结构进行特征分析。
对109名健康对照者和93例乳腺癌患者（均为白种人）的这些基因变异进行研究。根据TP53突变状态和对阿霉素的反应对病例进行分析。进行了单核苷酸多态性分析和多个单核苷酸多态性分析。
卡方分析显示，TP53突变状态与ABCB1外显子11的GA基因型（Ser400Asn）以及GSTP1的GG基因型（Ile105Val）之间存在显著关联（分别为P<0.01和P<0.05）。多因素降维分析表明，GSTP1的联合GG基因型和ABCB1外显子11的GG基因型携带者发生TP53基因突变的可能性最高（P<0.02）。ABCB1的单倍型分析显示，乳腺癌病例组和对照组之间单倍型分布存在显著差异（P<0.01）。在病例组中还观察到一种特定的单倍型与TP53突变（P<0.01）、远处转移（P<0.05）和雌激素受体状态（P<0.05）相关。
GSTP1和ABCB1基因多态性与肿瘤内TP53基因突变风险之间的关联表明存在潜在的易感基因型背景。ABCB1基因在健康个体中的连锁不平衡程度较高，而病例组中的单倍型似乎因一些低频变异而退化。这一观察结果可能表明对照组中存在保护性单倍型，或者可能强调低频变异积累作为易感因素的重要性。
