Use of Pyrosequencing to Detect Clinically Relevant Polymorphisms in Dihydropyrimidine Dehydrogenase

Ahluwalia, Ranjeet; Freimuth, Robert R.; McLeod, Howard L.; Marsh, Sharon

doi:10.1373/49.10.1661

Cited by 25 publications

(7 citation statements)

References 20 publications

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“…The detection of relevant DPYD gene SNPs by genotyping technique is promising, but many questions remain unresolved, such as which adequate method and which relevant SNPs (43).…”

Section: Discussionmentioning

confidence: 99%

Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance

Morel

Boisdron‐Celle

Fey

et al. 2006

Molecular Cancer Therapeutics

208

145

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Purpose: Although single nucleotide polymorphisms (SNP) of the dihydropyrimidine dehydrogenase gene (DPYD) have been reported, which affect enzyme activity and the severity of 5-fluorouracil (5-FU) toxicity, no pretherapeutic detection has thus far been developed. We investigated 22 DPYD gene SNPs, their respective incidence, their link with grade 3 to 4 toxic side effects, and their management in practice: 9 were looked for in 487 patients, whereas 13 others were investigated in 171 patients. Patients and Methods: SNPs were detected before 5-FU-based treatment in WBC using a Pyrosequencing method. Close clinical and biological follow-up was done. Results: Five different SNPs were found in 187 patients (IVS14 + 1G>A, 2846A>T, 1679T>G, 85T>C, −1590T>C). Three hundred patients had no SNP. Forty-four patients had grade 3 to 4 toxic side effects in either the first or second cycle. Sixty percent of patients with either IVS14 + 1G>A or 2846A>T SNPs and the only patient with 1679T>G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either −1590T>C, 85T>C SNP, or no SNP, respectively. In cases with grade 3 to 4 toxicity, treatment either had to be quickly stopped, or could be safely continued with an individual dose adjustment. Sensitivity, specificity, and positive and negative predictive values of the detection of these three major SNPs as toxicity predictive factors were 0.31, 0.98, and 0.62 and 0.94, respectively. Conclusion: Pretreatment detection of three DPYD SNPs could help to avoid severe toxic side effects. This approach is suitable for clinical practice and should be compared or combined with pharmacologic approaches. In the case of dihydropyrimidine dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment. [Mol Cancer Ther 2006;5(11):2895–904]

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“…The detection of relevant DPYD gene SNPs by genotyping technique is promising, but many questions remain unresolved, such as which adequate method and which relevant SNPs (43).…”

Section: Discussionmentioning

confidence: 99%

Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance

Morel

Boisdron‐Celle

Fey

et al. 2006

Molecular Cancer Therapeutics

208

145

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“…As done in routine practice at our institution to limit severe toxic side effects due to 5-FU, we looked for eight major SNPs of dihydropyrimidine dehydrogenase involved in reduced activity of this enzyme: intron 14G1A, A2846T, T85C, del TCAT295-298, G1156T, G2657A, G2983, and T 1590C (24). Moreover, 5-FU dose was individually adjusted based on a dose adjustment chart previously published (25).…”

Section: Patientsmentioning

confidence: 99%

Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity

Rouits

Boisdron‐Celle

Dumont

et al. 2004

Clinical Cancer Research

265

157

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Purpose: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert's syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients.Experimental Design: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment.Results: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert's syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity.Conclusions: The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert's syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity.

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“…In addition, there was no association between any of other mutations with DPD protein levels (17). In other studies no IVS14 + 1G > A mutation was detected among Japanese, Korean, and African-Americans as well (8,18,19). It seems that the mutation frequency is less reported in Asian and African ancestries.…”

Section: Discussionmentioning

confidence: 74%

A Survey on the Prevalence of IVS14 + 1G > A Mutation of the Dihydropyrimidine Dehydrogenase Gene Among a Group of Colorectal Cancer Patients in Northeast Iran, the Relevance of Fluoropyrimidine Based Chemotherapy Toxicity

Salek

Hosseini

Behravan

et al. 2016

Rep Radiother Oncol

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Background: Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5-fu). Deficiency of this enzyme can lead to severe and lethal toxicity following the administration of 5FU or capecitabine. The aim of this study was to demonstrate the prevalence of the IVS14 + 1G > A mutation of the dihydropyrimidine dehydrogenase gene (DPYD) and important side effects of the adjuvant chemotherapy regimens in an ethnic Iranian group of colorectal cancer (CRC) patients. Methods: The research population included patients with colorectal cancer during the period of October 2011 to January 2013. Genomic DNA was isolated from blood cells of 109 patients. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was carried out to identify the frequency of the IVS14 + 1G > A mutation. The side effects of chemotherapy regimens containing 5-FU or capecitabine were recorded during 1-6 courses of chemotherapy. Results: The IVS14 + 1G > A mutation was not found in the population studied. Overall 28.4% of patients reported to have at least 1 grade 3 or 4 toxicity. Conclusions: We concluded that IVS14 + 1G > A mutation was rare in the population studied; however, a larger sample size may be required to determine the precise mutation frequency in this region.

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Use of Pyrosequencing to Detect Clinically Relevant Polymorphisms in Dihydropyrimidine Dehydrogenase

Abstract: Mycobacterium primers and hybridization to an M. tuberculosis-specific probe. J Clin Microbiol 1996;34:918 -23.

Cited by 25 publications

References 20 publications

Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance

Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance

Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity

A Survey on the Prevalence of IVS14 + 1G > A Mutation of the Dihydropyrimidine Dehydrogenase Gene Among a Group of Colorectal Cancer Patients in Northeast Iran, the Relevance of Fluoropyrimidine Based Chemotherapy Toxicity

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