Polymorphism discovery in 51 chemotherapy pathway genes

Freimuth, Robert R.; Xiao, Ming; Marsh, Sharon; Minton, Matthew; Addleman, Nicholas J.; Booven, Derek J. Van; McLeod, Howard L.; Kwok, Pui‐Yan

doi:10.1093/hmg/ddi387

Cited by 20 publications

(13 citation statements)

References 30 publications

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“…On average, 248 unique polymorphisms reported in the public databases dbSNP, CGAG-GAI, and JSNP and identified by gene sequencing were mapped to each gene using PolyMAPr. At the time of analyses, sequencing identified 1 to 18 novel SNPs per gene (19). We determined the allelic frequencies of 41 SNPs and 2 indels by pyrosequencing germ-line DNA from European Americans, East Asians (Han Chinese), and West Africans (Ghanaians; Table 2).…”

Section: Analysis Of Candidate Gene Sequence Variationmentioning

confidence: 99%

“…) to the gene sequences (19,20). Alleles, single nucleotide polymorphisms (SNP), and insertion/ deletions (indels) were preferentially selected for construction of haplotype identities in the European, East Asian, and West African samples if they were in coding regions and in regulatory regions affecting gene expression if there was epidemiologic evidence to suggest that they altered the risk of developing a disease or they were predicted to affect function by PolyPhen (20).…”

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confidence: 99%

“…At the time of study commencement, genetic variation data for TOP1 and TDP1 were not available on the National Institute of Environmental Health Sciences Web site. Alleles with estimated frequencies of z5% in at least one ethnic group by resequencing were selected for haplotype construction of these two genes (19).…”

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confidence: 99%

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Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes

Hoskins¹,

Marcuello²,

Altés

et al. 2008

Clinical Cancer Research

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Purpose: Irinotecan is an important drug for the treatment of solid tumors. Although genes involved in irinotecan pharmacokinetics have been shown to influence toxicity, there are no data on pharmacodynamic genes. CDC45L, NFKB1, PARP1,TDP1, and XRCC1 have been shown to influence the cytotoxic action of camptothecins, including irinotecan. Polymorphisms in the drug target of camptothecins, topoisomerase I (TOP1), and downstream effectors may influence patient outcomes to irinotecan therapy. We undertook a retrospective candidate gene haplotype association study to investigate this hypothesis. Experimental Design: Haplotype compositions of six candidate genes were constructed in European (n = 93), East Asian (n = 94), and West African (n = 95) populations. Haplotypetagging single nucleotide polymorphisms (htSNP) were selected based on genealogic relationships between haplotypes. DNA samples from 107 European, advanced colorectal cancer patients treated with irinotecan-based regimens were genotyped for htSNPs as well as three coding region SNPs. Associations between genetic variants and toxicity (grade 3/4 diarrhea and neutropenia) or efficacy (objective response) were assessed. Results: TOP1 and TDP1 htSNPs were related to grade 3/4 neutropenia (P = 0.04) and response (P = 0.04), respectively. Patients homozygous for an XRCC1 haplotype (GGCC-G) were more likely to show an objective response to therapy than other patients (83% versus 30%; P = 0.02). This effect was also seen in a multivariate analysis (odds ratio, 11.9; P = 0.04). No genetic variants were associated with diarrhea. Conclusions: This is the first comprehensive pharmacogenetic investigation of irinotecan pharmacodynamic factors, and our findings suggest that genetic variation in the pharmacodynamic genes may influence the efficacy of irinotecan-containing therapies in advanced colorectal cancer patients.Irinotecan (CPT-11) is used for second-line treatment of metastatic colorectal cancer and as salvage therapy in 5-fluorouracil refractory disease. The major dose-limiting toxicities of CPT-11 -based therapies are delayed diarrhea and severe or fatal myelosuppression (1). CPT-11 itself is a relatively weak inhibitor of topoisomerase I (Topo I), and its clinical activity is dependent on in vivo conversion to the more potent metabolite, SN-38, a reaction catalyzed by carboxylesterase enzymes (CES1 and CES2; ref. 2).The pharmacokinetics of CPT-11 and its active metabolite, SN-38, are determined by numerous drug transporters and metabolizing enzymes (3). Many pharmacogenetic studies have investigated the influence of genetic variation in these pathways on patient-to-patient variation in CPT-11 pharmacokinetics and toxicity (4, 5). The strongest and most consistent association has been shown for a tandem repeat TA polymorphism 6>7 TAA] in the TATA box of the promoter region of the UDP-glucuronosyltransferases 1A1 gene (UGT1A1; refs. 4, 5). The deactivation to SN-38 glucuronide is principally catalyzed by UGT1A1 (6). Patients homozygous for the seve...

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Section: Analysis Of Candidate Gene Sequence Variationmentioning

confidence: 99%

mentioning

confidence: 99%

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Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes

Hoskins¹,

Marcuello²,

Altés

et al. 2008

Clinical Cancer Research

Self Cite

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“…This suggests that the extent of variation in the human genome is still unknown, and the distribution of those variants among population groups is not fully understood [22]. Consequently, resequencing in diverse ethnic populations is still ongoing in pharmacogenomic studies, and is essential for genes that are currently poorly represented in the databases and literature.…”

Section: Databasesmentioning

confidence: 99%

Pharmacogenomics

Marsh¹

2007

Annals of Oncology

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“…An alternative to a candidate gene approach is the application of newer genome-wide approaches (pharmacogenomics rather than pharmacogenetics) to take a broad "discovery- based" approach to genes that may modify response. 29,30 The advantages and disadvantages of these two approaches are compared in Table 1.…”

Section: Moving Forward: Broader Genomic Approachesmentioning

confidence: 99%

Pharmacogenetics, Pharmacogenomics and Personalized Medicine: Are We There Yet?

Davies¹

2006

Hematology

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The genetic basis of a differential response to drugs has been understood for a limited number of agents for over 30 years. This knowledge has generated hope that the individual basis for response to a wide range of drugs would be quickly known, and individualized drug selection and dosing would be possible for many or all disorders. Understanding the variable response to drugs seems particularly pressing in the field of oncology, in which the stakes are high (failure to cure cancer usually leads to death), drugs commonly have a narrow therapeutic index, and toxicities can be severe (a significant frequency of toxic death is a feature of most acute myeloid leukemia protocols, for example). However, in common with many new technologies, the generalizability and clinical application of pharmacogenetics has proved more challenging than expected. Difficulties include, in many examples, a modest clinical effect relative to genotype, therapy-specific, not broad, applicability and the very major challenge of unraveling the complexity of gene-gene interactions. In addition, ethical and economic challenges to the application of pharmacogenetics have moved to the fore in recent years, particularly in the context of racial differences in outcome of therapy. Genomic, rather than candidate gene approaches to identification of relevant loci are increasingly being explored, and significant progress is being made. However, greater understanding of the complexities of multiple gene modifiers of outcome, and the statistical challenge of understanding such data, will be needed before individualized therapy can be applied on a routine basis.

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Polymorphism discovery in 51 chemotherapy pathway genes

Cited by 20 publications

References 30 publications

Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes

Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes

Pharmacogenomics

Pharmacogenetics, Pharmacogenomics and Personalized Medicine: Are We There Yet?

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