Abstract 3173: Next generation sequencing (NGS) of dihydropyrimidine dehydrogenase (DPYD) gene in Mexican patients with gastrointestinal (GI) carcinomas

Abstract

Abstract Background: Fluoropyrimidines (5-fluorouracil (5-FU), capecitabine and tegafur) are the mainstay chemotherapeutic drugs for gastrointestinal cancer. Patients with deficiency of dihydropyrimidine dehydrogenase enzyme (DPD), which interfere with the pyrimidine metabolism, could be at risk toxicity (mild, severe or lethal) because >80% of the administered 5-FU is catabolized by DPD. Previously, our group studied DPYD single-nucleotide polymorphism (SNPs) by real-time PCR assay, in 72 Mexicans. We found that frequency of SNP 85T>C and 85T>T was similar as Oriental race (2-3%), but contrast with Caucasians (0.19%), meanwhile, for SNP 496A>G which Caucasian prevalence was reported 0.8%, in our Mexican sample was very high (14%). Even though, none of our patients with toxicity grade 3-4, were positive to the SNP associated to higher toxicity (IVS14 + 1G>A). Because of this heterogeneity, we decide to sequence the complete gen in our population. Methods: We included prospectively, 19 patients of the GI Oncology Department of the National Cancer Institute of Mexico, who were treated with fluoropyrimidines. We follow them during the whole treatment. DNA was extracted from whole blood using the DNeasy blood and tissue kit (Qiagen Ltd, Crawley, UK). We use the AmpliSeq™ Designer for the full coverage of all 23 exons of DPYD gene; 25 μg of DNA was used for library construction (Ion Ampliseq Library kit 2.0), we follow the manufacturer's instructions for the target sequencing of DPYD gene with the Ion Torrent PGM platform. The data management was performed with the Ion Reporter Software of Thermo Fisher. Results: We found that 89.5% of the patients had SNPs (c.85C>T), 44.1% (c.1627A>G) and 5.2% (c.496A>G). Mean while SNPs: c.1896T>C, c.451A>G, c.771C>T, c.2384G>A, c.2605G>A, c.1462A>G, c.1422_1422delA were present in a lower frequencies. These results were associated to clinical toxicity (mucositis, neurotoxicity, hand foot syndrome, hematological toxicity and diarrhea grade >2) but there wasn't any association (chi2 test). Not a single patient were positive for IVS14 + 1G>A. Conclusion: These are the first results using NGS for DPYD gene in Mexican people. We confirm that our population had a different molecular profile that Caucasians. We need to improve the sample size, to see if we could find an association between SNPs and clinical toxicity. Citation Format: Erika Ruiz-Garcia, Alicia Lopez-Yanez, Alette Ortega, Jorge Guadarrama-Orozco, Gisela Hernandez-Luis, Fabiola De la Rosa, Abelardo Meneses-Garcia, Horacio Astudillo-de la Vega. Next generation sequencing (NGS) of dihydropyrimidine dehydrogenase (DPYD) gene in Mexican patients with gastrointestinal (GI) carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3173.