RESUMEN
High-throughput drug screens are a powerful tool for cancer drug development. However, the results of such screens are often made available only as raw data, which is intractable for researchers without informatics skills, or as highly processed summary statistics, which can lack essential information for translating screening results into clinically meaningful discoveries. To improve the usability of these datasets, we developed Simplicity, a robust and user-friendly web interface for visualizing, exploring, and summarizing raw and processed data from high- throughput drug screens. Importantly, Simplicity allows for easy recalculation of summary statistics at user-defined drug concentrations. This allows Simplicity's outputs to be used with methods that rely on statistics being calculated at clinically relevant doses. Simplicity can be freely accessed at https://oncotherapyinformatics.org/simplicity/.
RESUMEN
Expression quantitative trait loci (eQTLs) identified using tumor gene expression data could affect gene expression in cancer cells, tumor-associated normal cells, or both. Here, we have demonstrated a method to identify eQTLs affecting expression in cancer cells by modeling the statistical interaction between genotype and tumor purity. Only one third of breast cancer risk variants, identified as eQTLs from a conventional analysis, could be confidently attributed to cancer cells. The remaining variants could affect cells of the tumor microenvironment, such as immune cells and fibroblasts. Deconvolution of tumor eQTLs will help determine how inherited polymorphisms influence cancer risk, development, and treatment response.
Asunto(s)
Expresión Génica , Modelos Estadísticos , Neoplasias/genética , Sitios de Carácter Cuantitativo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinogénesis/genética , Simulación por Computador , Femenino , Fibroblastos/metabolismo , Variación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Neoplasias/metabolismo , Microambiente TumoralRESUMEN
The advent of targeted therapeutics has greatly improved outcomes of chronic myeloid leukemia (CML) patients. Despite increased efficacy and better clinical responses over cytotoxic chemotherapies, many patients receiving targeted drugs exhibit a poor initial response, develop drug resistance, or undergo relapse after initial success. This inter-individual variation in response has heightened the interest in studying pharmacogenetics and pharmacogenomics (PGx) of cancer drugs. In this review, we discuss the influence of various germline and somatic factors on targeted drug response in CML. Specifically, we examine the role of genetic variants in drug metabolism genes, i.e. CYP3A family genes, and drug transporters, i.e. ABC and SLC family genes. Additionally, we focus on acquired somatic variations in BCR-ABL1, and the potential role played by additional downstream signaling pathways, in conferring resistance to targeted drugs in CML. This review highlights the importance of PGx of targeted therapeutics and its potential application to improving treatment decisions and patient outcomes.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Antineoplásicos/uso terapéutico , Citocromo P-450 CYP3A/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Fusión bcr-abl/genética , Glucuronosiltransferasa/genética , Humanos , Inactivación Metabólica/genética , Transportador 1 de Catión Orgánico/genética , Farmacogenética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
OBJECTIVES: Clinical studies show that Asians (ASN) are more susceptible to toxicities associated with platinum-containing regimens. We hypothesized that studying ASN as an 'enriched phenotype' population could enable the discovery of novel genetic determinants of platinum susceptibility. METHODS: Using well-genotyped lymphoblastoid cell lines from the HapMap, we determined cisplatin and carboplatin cytotoxicity phenotypes (IC50s) for ASN, Caucasians (CEU), and Africans (YRI). IC50s were used in genome-wide association studies. RESULTS: ASN were most sensitive to platinums, corroborating clinical findings. ASN genome-wide association studies produced 479 single-nucleotide polymorphisms (SNPs) associating with cisplatin susceptibility and 199 with carboplatin susceptibility (P<10). Considering only the most significant variants (P<9.99x10), backwards elimination was then used to identify reduced-model SNPs, which robustly described the drug phenotypes within ASN. These SNPs comprised highly descriptive genetic signatures of susceptibility, with 12 SNPs explaining more than 95% of the susceptibility phenotype variation for cisplatin, and eight SNPs approximately 75% for carboplatin. To determine the possible function of these variants in ASN, the SNPs were tested for association with differential expression of target genes. SNPs were highly associated with the expression of multiple target genes, and notably, the histone H3 family was implicated for both drugs, suggesting a platinum-class mechanism. Histone H3 has repeatedly been described as regulating the formation of platinum-DNA adducts, but this is the first evidence that specific genetic variants might mediate these interactions in a pharmacogenetic manner. Finally, to determine whether any ASN-identified SNPs might also be important in other human populations, we interrogated all 479/199 SNPs for association with platinum susceptibility in an independent combined CEU/YRI population. Three unique SNPs for cisplatin and 10 for carboplatin replicated in CEU/YRI. CONCLUSION: Enriched 'platinum susceptible' populations can be used to discover novel genetic determinants governing interindividual platinum chemotherapy susceptibility.
