title: Identification of candidate SNPs for drug induced toxicity from differentially expressed genes in associated tissues.
abstract: The growing collection of publicly available high-throughput data provides an invaluable resource for generating preliminary in silico data in support of novel hypotheses. In this study we used a cross-dataset meta-analysis strategy to identify novel candidate genes and genetic variations relevant to paclitaxel/carboplatin-induced myelosuppression and neuropathy. We identified genes affected by drug exposure and present in tissues associated with toxicity. From ten top-ranked genes 42 non-synonymous single nucleotide polymorphisms (SNPs) were identified in silico and genotyped in 94 cancer patients treated with carboplatin/paclitaxel. We observed variations in 11 SNPs, of which seven were present in a sufficient frequency for statistical evaluation. Of these seven SNPs, three were present in ABCA1 and ATM, and showed significant or borderline significant association with either myelosuppression or neuropathy. The strikingly high number of associations between genotype and clinically observed toxicity provides support for our data-driven computations strategy to identify biomarkers for drug toxicity.
authors: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, SE-171 65 Solna, Sweden.
authors: Johanna
authors: J
authors: Hasmats
authors: Ilya
authors: I
authors: Kupershmidt
authors: Cristina
authors: C
authors: Rodríguez-Antona
authors: Qiaojuan Jane
authors: QJ
authors: Su
authors: Muhammad Suleman
authors: MS
authors: Khan
authors: Carlos
authors: C
authors: Jara
authors: Xabier
authors: X
authors: Mielgo
authors: Joakim
authors: J
authors: Lundeberg
authors: Henrik
authors: H
authors: Green
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000633:toxicity*; D064007:Ataxia Telangiectasia Mutated Proteins; D001853:Bone Marrow / Q000187:drug effects; D016190:Carboplatin / Q000493:pharmacokinetics / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D030541:Databases, Genetic; D005260:Female; D015870:Gene Expression; D005819:Genetic Markers; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D025521:Tumor Suppressor Proteins; D016190:Carboplatin; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel