ArticlePharmacogenetics and genomics2010
Population differences in platinum toxicity as a means to identify novel genetic susceptibility variants.
Article in Pharmacogenetics and genomics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 2 of them syntheses that pooled it.
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Who cites it
15 citing papers in PubMed, 2 syntheses or guidelines pooled it, 30 citations in OpenAlex.
- Genome-wide meta-analysis identifies variants associated with platinating agent susceptibility across populations.The pharmacogenomics journal · 2013Pooled it
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- Extending the lymphoblastoid cell line model for drug combination pharmacogenomics.Pharmacogenomics · 2021Review
- Clinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in Neoadjuvant Chemotherapy for Urothelial Cancer.Clinical genitourinary cancer · 2016Article
- Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study.Environmental health perspectives · 2015Article
- In vitro human cell line models to predict clinical response to anticancer drugs.Pharmacogenomics · 2015Review
- Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer.BioMed research international · 2015Review
- Lymphoblastoid cell lines models of drug response: successes and lessons from this pharmacogenomic model.Current molecular medicine · 2014Article
- Article
- Update on first-line treatment of advanced ovarian carcinoma.International journal of women's health · 2013Article
- Functional consequences of PRPF39 on distant genes and cisplatin sensitivity.Human molecular genetics · 2012Article
- Lymphoblastoid cell lines in pharmacogenomic discovery and clinical translation.Pharmacogenomics · 2012Review
- Germline polymorphisms discovered via a cell-based, genome-wide approach predict platinum response in head and neck cancers.Translational research : the journal of laboratory and clinical medicine · 2011Article
- Comprehensive evaluation of the contribution of X chromosome genes to platinum sensitivity.Molecular cancer therapeutics · 2011Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
objectivesClinical 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.
methodsUsing 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.
resultsASN 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.
conclusionEnriched 'platinum susceptible' populations can be used to discover novel genetic determinants governing interindividual platinum chemotherapy susceptibility.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.