ABCB1 and GST polymorphisms associated with TP53 status in breast cancer.
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, GSTT1 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 (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.


CONCLUSIONS
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.
Nordgard
Silje H
SH
Department of Genetics, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway.
Ritchie
Marylyn D
MD
Jensrud
Sigrid D
SD
Motsinger
Alison A
AA
Alnaes
Grethe I G
GI
Lemmon
Gordon
G
Berg
Marianne
M
Geisler
Stephanie
S
Moore
Jason H
JH
Lønning
Per Eystein
PE
Børresen-Dale
Anne-Lise
AL
Kristensen
Vessela N
VN
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009664:Norway; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011995:Recombination, Genetic; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D027361:Organic Anion Transporters; D016159:Tumor Suppressor Protein p53; C513055:ABCB1 protein, human; C413545:glutathione S-transferase T1