Pyrosequencing of Clinically Relevant Polymorphisms

Marsh, Sharon; King, Cristi R.; Garsa, Adam A.; McLeod, Howard L.

doi:10.1385/1-59259-957-5:097

Cited by 47 publications

(43 citation statements)

References 6 publications

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“…With the exception of XRCC1 -77T>C, genotyping was done using PCR and pyrosequencing as previously described (28). Primer sets for the htSNPs and putative causal SNPs are presented in Supplementary Table S1.…”

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confidence: 99%

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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confidence: 99%

Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes

Hoskins¹,

Marcuello²,

Altés

et al. 2008

Clinical Cancer Research

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“…Pyrograms were analyzed by Pyro-Mark 1.0 software with allele quantification mode to determine the percentage of mutant versus WT alleles according to relative peak height (23). Repeat genotyping of BRAF V600E and genotyping of NRAS Q61R, NRAS Q61K, and HRAS Q61R was carried out with PCR, and Pyrosequencing as previously described using the primer sets described by Volante and colleagues (24, 25). …”

Section: Methodsmentioning

confidence: 99%

Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements

Hayes

Lucas

Tanvetyanon

et al. 2012

Clinical Cancer Research

141

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Purpose A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC). Experimental Design Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed. Results Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug. Conclusions Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome.

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“…28,33,44 Statistics Associations between genotype and paclitaxel clearance were performed using Kruskal-Wallis and ANOVA tests. Genotype-outcome associations were performed using w 2 and Kaplan-Meier analysis.…”

Section: Genotypingmentioning

confidence: 99%

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

Marsh

Somlo

et al. 2007

Pharmacogenomics J

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Paclitaxel is commonly used in the treatment of breast cancer. Variability in paclitaxel clearance may contribute to the unpredictability of clinical outcomes. We assessed genomic DNA from the plasma of 93 patients with high-risk primary or stage IV breast cancer, who received dose-intense paclitaxel, doxorubicin and cyclophosphamide. Eight polymorphisms in six genes associated with metabolism and transport of paclitaxel were analyzed using Pyrosequencing. We found no association between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance. However, patients homozygous for the CYP1B1*3 allele had a significantly longer progression-free survival than patients with at least one Valine allele (P ¼ 0.037). This finding could reflect altered paclitaxel metabolism, however, the finding was independent of paclitaxel clearance. Alternatively, the role of CYP1B1 in estrogen metabolism may influence the risk of invasive or paclitaxel resistant breast cancer in patients carrying the CYP1B1*3 allele.

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Pyrosequencing of Clinically Relevant Polymorphisms

Cited by 47 publications

References 6 publications

Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes

Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes

Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

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