Comparison of Eight Technologies to Determine Genotype at the UGT1A1 (TA)n Repeat Polymorphism: Potential Clinical Consequences of Genotyping Errors?

Sissung, Tristan M.; Barbier, Roberto H.; Price, Douglas K.; Plona, Teri M.; Pike, Kristen; Mellott, Stephanie D.; Baugher, Ryan N.; Whiteley, Gordon; Soppet, Daniel; Venzon, David; Berman, Arlene; Rajan, Arun; Giaccone, Giuseppe; Meltzer, Paul S.; Figg, William D.

doi:10.3390/ijms21030896

Cited by 8 publications

(5 citation statements)

References 17 publications

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“…12 , 14–16 , 31 There is a need for unambiguous results, particularly for this polymorphism, because several technologies are inappropriate for use in obtaining specific genotypes. 32 It is true that the (TA)5 and (TA)8 alleles are more frequent in African Americans, but with the current racial admixture this should not be overlooked. Moreover, until now, therapeutic recommendations for other genotypes than UGT1A1*28/*28 were not established, but one of the reasons may be the lack of data on *36 and *37 alleles.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic Practice of Anticancer Drugs: Multiple Approaches for an Accurate and Comprehensive Genotyping

Montrasio¹,

Cheli²,

Clementi³

2023

PGPM

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The application of pharmacogenetics in oncology is part of the routine clinical practice. In particular, genotyping of dihydropyrimidine dehydrogenase (DPYD) and UDP-glucuronosyltransferase (UGT1A1) is crucial to manage the treatment of patients taking fluoropyrimidines and irinotecan. The unique approach of our laboratory to the pharmacogenetic diagnostic service in oncology is to combine two real-time PCR methods, LightSNiP assay (TIB MOLBIOL), and more recently FRET (Fluorescent Resonance Energy Transfer) probes technology (Nuclear Laser Medicine), plus TaqMan assay (Thermo Fisher) for the confirmation of the presence of variant alleles on DNA from a second extraction. We found that both the FRET and LightSNiP assays, where detection occurs by melting curve analysis, offer an advantage over the competing TaqMan technology. Whereas unexpected genetic variants may be missed using a mutation-specific TaqMan assay, the information thus obtained can be useful to adjust the therapy in case of unexpected post-treatment toxicity. The combination of TaqMan and FRET assays helped us to achieve more accurate genotyping and a correct result for the patient. The added value of the DPYD FRET assay is the possibility of detecting, with the same amplification profile of the polymorphisms detailed in the guidelines, also the c.2194G>A (*6 rs1801160), cited in the recommendations as a variant to be investigated in case of severe toxicity. Regarding the UGT1A1 (TA)n promoter polymorphism (rs3064744), the distinctive and positive feature of the FRET assay is to allow clearly identifying all those potential variant alleles, including the (TA)5 and (TA)8 alleles, that are frequent in African Americans. Our clinical practice emphasizes the importance of not only rapid and easy-to-use assays, such as the new FRET ones, but also of accurate and comprehensive genotyping for good pharmacogenetic diagnostic activity.

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Section: Discussionmentioning

confidence: 99%

Pharmacogenetic Practice of Anticancer Drugs: Multiple Approaches for an Accurate and Comprehensive Genotyping

Montrasio¹,

Cheli²,

Clementi³

2023

PGPM

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“…Several methods have been developed in recent years, and up to eight different methods for rs3064744 genotyping were recently compared [ 17 ]. Mismatches were observed between the different methodologies.…”

Section: Discussionmentioning

confidence: 99%

Genotyping of UGT1A180 as an Alternative to UGT1A128 Genotyping in Spain

et al. 2022

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Background: The variant rs34983651 (UGT1A1*28) and its genotyping are used to prevent irinotecan-induced toxicity. Several variants are in close linkage disequilibrium. Our objective was to evaluate the potential correlation of genotyping UGT1A1*80 instead of UGT1A1*28 in different populations. Methods: We studied SNPs in linkage disequilibrium with UGT1A1*28 in several populations and selected rs887829 to develop an inexpensive and rapid genotyping method and compare it with the one we currently use for UGT1A1*28 genotyping. Samples from cancer patients (n = 701) already tested using PCR and electrophoresis prior to treatment with irinotecan for rs34983651 (UGT1A1*28) in a Spanish hospital were genotyped for rs887829 (UGT1A1*80) using real-time PCR with a TaqMan probe. Results: We observed a complete match for both genotypes, except in one sample. This method was 100% efficient in correctly genotyping *28/*28 patients, 99.68% efficient for *1/*28, and 100% efficient for *1/*1. Linkage disequilibrium between populations showed the Iberian population to be the most suitable for the clinical use of UGT1A1*80. This method is less expensive and the time to decision is shorter. Conclusion: Genotyping of rs887829 using the proposed method may be used to substitute genotyping of rs34983651 as a pharmacogenetics test in cancer patients prior to starting irinotecan-based treatments, mainly in the Iberian population. In addition, it is less expensive than other conventional methods and easy to implement, with a shorter time to decision than UGT1A1*28.

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“…SLCO1B3 single nucleotide polymorphisms (SNP) 334T>G (rs4149117) and 688 G>A (rs7311358) were genotyped via direct sequencing, as previously published 6 . Additionally, to evaluate the 51 main SNPs in SLCO1B3 , SLCO1B1 and SLC10A1 (NTCP), isolated genomic DNA was genotyped by Pharmacoscan assay (Thermo Fisher Scientific, Waltham, MA, USA), as previously described 22 .…”

Section: Methodsmentioning

confidence: 99%

Pilot study of gadoxetate disodium-enhanced mri for localized and metastatic prostate cancers

Lochrin

Türkbey

Gasmi

et al. 2021

Sci Rep

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OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < 0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time (p > 0.05). OATP1B3 expression on IHC trended higher contrast enhancement between 20–40 min (p ≤ 0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40–60 min (p ≤ 0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer.

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Comparison of Eight Technologies to Determine Genotype at the UGT1A1 (TA)n Repeat Polymorphism: Potential Clinical Consequences of Genotyping Errors?

Cited by 8 publications

References 17 publications

Pharmacogenetic Practice of Anticancer Drugs: Multiple Approaches for an Accurate and Comprehensive Genotyping

Pharmacogenetic Practice of Anticancer Drugs: Multiple Approaches for an Accurate and Comprehensive Genotyping

Genotyping of UGT1A180 as an Alternative to UGT1A128 Genotyping in Spain

Pilot study of gadoxetate disodium-enhanced mri for localized and metastatic prostate cancers

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Comparison of Eight Technologies to Determine Genotype at the UGT1A1 (TA)n Repeat Polymorphism: Potential Clinical Consequences of Genotyping Errors?

Cited by 8 publications

References 17 publications

Pharmacogenetic Practice of Anticancer Drugs: Multiple Approaches for an Accurate and Comprehensive Genotyping

Pharmacogenetic Practice of Anticancer Drugs: Multiple Approaches for an Accurate and Comprehensive Genotyping

Genotyping of UGT1A1*80 as an Alternative to UGT1A1*28 Genotyping in Spain

Pilot study of gadoxetate disodium-enhanced mri for localized and metastatic prostate cancers

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Product

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Genotyping of UGT1A180 as an Alternative to UGT1A128 Genotyping in Spain