Abstract P3-08-05: Title: Copy number variation and risk of chemotherapy-related infection.

Abstract

Abstract Background: Copy-number variations (CNVs) are DNA changes that result in regions of the genome being either duplicated (copy number gains) or deleted (copy number losses). CNVs have been identified in 12% of the human genome. Although CNVs do not appear to have a major role in disease susceptibility, it is known that they are involved in drug metabolism, toxicity and response. Infection is a common dose and/or treatment limiting chemotherapy-related toxicity. Infections can be a major cause of morbidity and mortality. Although a limited number of studies have investigated the association of single nucleotide polymorphisms (SNPs) with severity of infection, no studies so far have identified CNV associations with chemotherapy-related infection. In a non-oncological setting, CNVs have been noted to be associated with altered risk of certain types of infections and severe sepsis. This study aims to evaluate whether CNV are associated with the risk of chemotherapy-related infection in a genome wide association study (GWAS) of breast cancer patients recruited to clinical trials and treated with chemotherapy regimens including paclitaxel, epirubicin, cyclophosphamide, gemcitabine, 5fluorouracil and methotrexate. Method: DNA from blood and saliva samples were collected as part of the pharmacogenetics GWAS, PGSNPS. Chemotherapy-related infection was assessed using the NCI Common Toxicity Criteria (CTC). Patients (n = 1921 samples) were classified as cases (NCI CTC grades 2–4) or as controls (NCI CTC grades 0–1). The Affymetrix SNP6.0 array, which contains more than 946,000 probes for the detection of CNVs and more than 906,600 SNPs, was used as the copy number estimation platform. DNA was segmented using DNAcopy (circular binary segmentation). CNVs were called based on their median and standard deviation. Log-ratios larger than the median plus 2 times the standard deviation were considered gains and log-ratios with values smaller than 2.5 times the standard deviation were considered as losses. Only regions with a copy number alteration present in at least a 10% of the samples were considered for the analysis. Fisher's exact test was performed on each of these regions and the variable ‘infection’. 2-side p-values were obtained and adjusted using Benjamin-Hochberg correction. Results: One CNV region (frequency of gain 0.16) showed an association with increased risk of infection (Odds Ratio=1.79, 95% Confidence Interval [1.34–2.40], P = 6.37 × 10−5). Five other CNV regions demonstrated copy number gains and three CNV regions showed copy number losses that were associated with an increased risk of infection (P = 10−4). All regions had a frequency of gain or loss > 0.10 and were therefore not rare variants. Conclusion: These data suggest that CNVs may play a role in increased risk of chemotherapy-related toxicity. The most significant CNVs associated with infection are currently undergoing validation using an independent cohort of adjuvant breast cancer patients with similar exposure to chemotherapy and comparable documentation of chemotherapy-related infection. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-05.