Original Article Design and validity of a clinic-based case-control study on the molecular epidemiology of lymphoma
Prema Peethambaram, Brooke L. Fridley, Robert A. Vierkant, Melissa C. Larson, Kimberly R. Kalli, Elaine A. Elliott, Ann L. Oberg, Kristin L. White, David N. Rider, Gary L. Keeney, Julie M. Cunningham, Lynn C. Hartmann, Ellen L. Goode
Departments of 1Oncology, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
Received March 11, 2011; accepted April 22, 2011; Epub May 2, 2011; published May 15, 2011
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 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, whichever came first). 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% CI 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% CI 0.59-0.92; p=0.006). No associations with outcome were observed in GSTM1, CYP2C8, CYP3A4, ERCC1, XPC, or XRCC1. Inherited variation in ABCB1 and ERCC2 was associated with outcome in patients with ovarian cancer seen at Mayo. 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. (IJMEG1103003).
Address all correspondence to: Ellen L. Goode, PhD Department of Health Sciences Research Mayo Clinic College of Medicine 200 First Street SW Rochester, MN 55905, USA Tel: 507/266-7997 Fax: 507/266-2478 E-mail: email@example.com