Abstract 5545: Rare genetic variation association with neurotoxicity and infection in breast cancer patients enrolled in PG-SNPS
Authors: Pirie Ailith , Abraham Jean , Michailidou Kyriaki , Tyrer Jonathan , Dorling Leila , Dennis Joe , Earl Helena , Caldas Carlos , Pharoah Paul 
Published: May 2015

Abstract
The genetic architecture underlying individual variation in susceptibility to severe toxicity to chemotherapeutic agents is not yet fully understood. We used a gene-based omnibus test to investigate the role of rare genetic variation in severe neurosensory toxicity and infection. Samples from a breast cancer pharmacogenetics study (PG-SNPS), were genotyped using the Illumina Human Exome Beadchip array. Early breast cancer patients treated with adjuvant and neo-adjuvant chemotherapy trials were recruited into PG-SNPS. Clinical data relating to their chemotherapy-related toxicities was collected prospectively. The National Cancer Institute Common Toxicity Criteria (NCI CTC version 2) was used to assess toxicities. For each of the toxicities, a case-control analysis was conducted using the Rare Admixture Maximum Likelihood method(1). RAML is an omnibus test that looks at joint effects of multiple variants on a phenotype. The test considers the probability that a given variant is associated with severe toxicity, the average effect of the associated variants within a gene on severe toxicity, and the expected standard error of this effect. Patients were considered as taxane-related neurosensory cases, if they had a CTC grade of ≥ 2 and as infection cases if they have a CTC grade of ≥ 3. For both analyses variants with minor allele frequency less than 2% were included. Only patients treated with paclitaxel were included in the neurosensory analysis. In this analysis we included 1,127 patients, 333 of which were considered cases. We tested variants in 14,762 genes exome-wide. The gene LRRTM3 was associated with severe neurosensory toxicity (p-value=5.5 x 10-4). LRRTM3 is a protein-coding gene with strong links to the maintenance and development of the nervous system. Patients exposed to specific adjuvant/neo-adjuvant breast cancer combination chemotherapy regimens with paclitaxel, epirubicin, methotrexate, cyclophosphamide, 5fluorouracil or gemcitabine, were included in the infection analysis (2,3,4). These included 1,564 patients, 583 of which were considered cases. We tested 15,161 genes exome-wide for association with severe infection. The top associated gene was FKBP5 with a p-value of 7 x 10-5. This gene has a role in immunoregulation and encodes a protein which binds to the immunosuppressants FK506 and rapamycin. These genes may be of future interest as candidate genes within pharmacodynamic pathways.
1. Tyrer JP, Guo Q, Easton DF, Pharoah PD. The admixture maximum likelihood test to test for association between rare variants and disease phenotypes. BMC Bioinformatics 2013;14:177.
2. NEAT trial - ClinicalTrials.gov Identifier NCT00003577
3. tAnGo trial - ClinicalTrials.gov Identifier NCT00039546
4. Neo-tAnGo trial - ClinicalTrials.gov Identifier NCT00070278
Citation Format: Ailith Pirie, Jean Abraham, Kyriaki Michailidou, Jonathan Tyrer, Leila Dorling, Joe Dennis, Helena Earl, Carlos Caldas, Paul Pharoah. Rare genetic variation association with neurotoxicity and infection in breast cancer patients enrolled in PG-SNPS. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5545. doi:10.1158/1538-7445.AM2014-5545