ABCB1 and GST polymorphisms associated with TP53 status in breast cancer

作者：Nordgard Silje H; Ritchie Marylyn D; Jensrud Sigrid D; Motsinger Alison A; Alnaes Grethe I G; Lernmon Gordon; Berg Marianne; Gelsler Stephanie; Moore Jason H; Lonning Per Eysteln; Borresen Dale Anne Lise; Kristensen Vessela N^*

来源：Pharmacogenetics and Genomics, 2007, 17(2): 127-136.

DOI：10.1097/fpc.0b013e328011abaa

• ABCB1
• breast cancer
• doxorubicin
• glutathione S-transferase
• haplotype
• MDR1
• single nucleotide polymorphism
• TP53

Background and Objective 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, GSTTI and GSTP1 genes, as well as the haplotype structure in the ABCB1 gene.
Methods 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.
Results Chi-square analyses revealed a significant association between TP53 mutation status and both the GA genotype of ABCB1 exon 11 (Ser(400)Asn) and the GG genotype of GSTP1 (IIe(105)Val; 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.
Conclusion An association between polymorphisms in GSTP1 and ABCB1 and risk o 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.

• 出版日期2007-2
• 单位河北医科大学