Fluoropyrimidine-Induced Severe Toxicities Associated with Rare DPYD Polymorphisms: Case Series from Saudi Arabia and a Review of the Literature.

Dihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of 5-Fluorouracil (5-FU) and its prodrug capecitabine. We report cases from our institute with colorectal cancer who experienced severe toxicities to standard dose 5-FU based chemotherapy. DPYD gene sequencing revealed rare different polymorphisms that prompted dose adjustments of administered 5-FU and capecitabine. To our knowledge, this is the first case series looking at DPYD polymorphisms in the Saudi Arabian population.

Evaluation of the Idylla KRAS and NRAS mutation test in colorectal cancer tissue.

INTRODUCTION: The currently approved techniques for RAS mutations testing in colorectal cancer (CRC) tissue are labor-intensive and time consuming. The Idylla technology (IT) is a rapid and fully automated diagnostics system. The primary aim of this study is to compare the Idylla performance against that of conventional techniques (CT). METHODOLOGY: Archival CRC tumor samples from 2 hospitals were tested for KRAS and NRAS mutations using the IT. Results were compared to those obtained earlier by CT performed in accredited laboratories. Unexplained discordant results were verified locally by next generation sequencing (NGS) to ascertain the accuracy of IT. RESULTS: Forty five samples were processed. All samples underwent dual testing (CT & IT) for KRAS mutations. IT identified mutations in 2 samples that were not detected by CT. Primary concordance rate for KRAS was 93.3% and the accuracy rate improved to 100% after verification and explanation of discordant results. Only 18 samples underwent dual testing for NRAS. Primary concordance and accuracy rates for NRAS were 94.4%. The mean time from dispatching the specimen for RAS testing by CT until receipt of results was 12 (7-28) days compared to few hours when IT was used. CONCLUSION: IT provides a quick and reliable mean for RAS testing. In addition, it identifies mutations that are not detected by CT and thus may provide better guidance to treatment choices.

Precursor B cell lymphoid blast crisis of chronic myeloid leukemia with novel chromosomal abnormalities: A case report.

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder. It is characterized by the presence of the Philadelphia (Ph) chromosome, t(9;22)(q34.1;q11.2), which carries the BCR-ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) have markedly changed the treatment approach of CML and have become the first-line agents for almost all CML patients. However, certain patients experience resistance to these medications, which occurs through several mechanisms, including the accumulation of TKI-resistant chromosomal abnormalities. The present study reports a case of a 27-year-old Saudi male with CML receiving TKI treatment, who presented with precursor B-cell lymphoblastic crisis demonstrating the presence of the novel combined chromosomal abnormalities; non-Ph der(22), i(9) and der(20), carrying the BCR-ABL1 fusion gene. This case report adds to the literature on novel TKI-resistance-conferring chromosomal abnormalities and links them to precursor B-cell lymphoblastic crisis.

Isocitrate dehydrogenases in physiology and cancer: biochemical and molecular insight.

Isocitrate dehydrogenases play important roles in cellular metabolism and cancer. This review will discuss how the roles of isoforms 1 and 2 in normal cell and cancer metabolism are distinct from those of isoform 3. It will also explain why, unlike 1 and 2, mutations in isoform 3 in tumor are not likely to be driver ones. A model explaining two important features of isocitrate dehydrogenases 1 and 2 mutations, their dominant negative effect and their mutual exclusivity, will be provided. The importance of targeting these mutations and the possibility of augmenting such therapy by targeting other cancer-related pathways will also be discussed.