Polymorphisms in ABCB1 and ERCC2 associated with ovarian cancer outcome

Abstract

Using the most comprehensive approach to selecting polymorphisms to date, we sought to examine whether time to recurrence in ovarian cancer was associated with common inherited variation in eight genes involved in drug metabolism, multi-drug resistance, or DNA repair, namely ABCB1, CYP2C8, CYP3A4, ERCC1, ERCC2, GSTM1, XPC, and XRCC1. Invasive epithelial ovarian cancer patients (N=445) seen at the Mayo Clinic from 1999 to 2009 with 275 observed recurrences or deaths were analyzed at 94 SNPs in these candidate genes. Cox regression was used to estimate hazard ratios and 95% confidence intervals for each single nucleotide polymorphism (SNP) and outcome (defined as time to recurrence or death). Analyses were conducted at the gene level and on case subsets defined by histopathology and chemotherapeutic agent. At ABCB1, minor alleles at several SNPs were associated with outcome, with the most significant being the intronic SNP rs12334183 (HR=0.65, 95% Cl 0.51-0.83; p=0.0005). Overall variation in ABCB1 was predictive of outcome as well (p=0.003). At ERCC2, minor alleles at several SNPs were associated with outcome among women with high-grade serous disease (e.g., rs238417, HR 0.74, 95% Cl 0.59-0.92; p=0.006). No associations with outcome were observed in GSTM1, CYP2C8, CYP3A4, ERCC1, XPC, or XRCC1. In summary, inherited variation in ABCB1 and ERCC2 was associated with outcome in patients with ovarian cancer seen at the Mayo Clinic. As the associated SNPs have not been studied previously in ovarian cancer, these findings suggest novel sites of variation which may, in part, explain the range of treatment responses seen in this disease.

Keywords: Ovarian cancer; drug-related variants; metabolism.

Figure 1

Linkage disequilibrium plot of ABCB1. Haploview 4.2 based on 445 cases; r²=0=white and r²⁼1=black; numbers represent r² * 100; genome build 36.3.