Pharmacogenetic Study of 5-Fluorouracil-Related Severe Toxicity in Thai Cancer Patients: A Novel SNP Detection

Sirachainan, Ekaphop; Reungwetwattana, Thanyanan; Wisetpanit, Y.; Panvichian, Ravat; Sirisinha, Thitiya; Ativitavas, Touch; Ratanatharathorn, V.; Trachu, Narumol; Sukasem, Chonlaphat

doi:10.4172/2153-0645.1000112

Cited by 5 publications

(13 citation statements)

References 23 publications

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“…The ability of DPYD*2A to indicate fluorouracil-induced toxicity in China could not be assessed. DPYD*5 and DPYD c.1896 T > C had allele frequencies of 28.4% and 10.7%, respectively, which was consistent with previous reports [ 31 ]. In this cohort, it was noted that DPYD*5 associated with higher risk of severe diarrhea.…”

Section: Discussionsupporting

confidence: 92%

“…In this cohort, it was noted that DPYD*5 associated with higher risk of severe diarrhea. However, in Zhang XP et al and Yamauchi et al’s study, DPYD*5 related to the incidence of severe neutropenia [ 31 , 32 ]. In addition, the study of Felicia FS et al showed that DPYD c.1896 T > C independently predicted severe fluorouracil-induced toxicity, which did not happen in this analysis [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

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Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Liú

Gao

et al. 2017

BMC Cancer

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BackgroundTo evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC).MethodsThe genotypes of UGT1A (UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A7*4 and UGT1A9*22) and DPYD (DPYD*5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed.ResultsIn the cohort studied here, the incidence of UGT1A1*6, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A9*22, DPYD*5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A1*27 and DPYD*2A had low frequencies and UGT1A7*4 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A1*28 heterozygotes (OR = 2.263, 95%CI 1.395–3.670), UGT1A1*28 homozygotes (OR = 5.910, 95%CI 1.138–30.672) and UGT1A1*6 homozygotes (OR = 4.737, 95%CI 1.946–11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD*5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136–4.041). Neither DPYD*5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A1*28 and DPYD*5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD*5 was found to associate with better progression-free survival (P = 0.015). UGT1A1*27 contributed to worse overall survival (P < 0.001).ConclusionResults still showed UGT1A1*6 and UGT1A1*28 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A1*6 and UGT1A1*28, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3406-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Liú

Gao

et al. 2017

BMC Cancer

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“…Heterozygous carriers of the intron 14 splice donor variant c.1905+1G>A were reported in one Thai cohort patient 77 and 14 Chinese cohort patients in which significantly higher incidences of grade 3-4 myelosuppression, hand-foot syndrome, diarrhoea, gastrointestinal reactions and mucositis were observed (OR = unreported; p < 0.001 for each severe side effect) compared to wild-type carriers 69 . 100% of the in silico prediction tools we utilised predicted this variant to be deleterious and published in vitro expression analysis reported c.1905+1G>A to be catalytically inactive (Table 3) 56,65 .…”

Section: Resultsmentioning

confidence: 97%

“…It is interesting to note that our systematic review has identified 3 of the 4 DPYD variants tested in the UK and EU 36,37 , in non-European individuals. The c.1905+1G>A variant, which leads to exon 14 skipping, has been reported in 1 Thai 77 , 14 Chinese 69 , 1 Lebanese 82 , 7 Bangladeshi 91 and 18 Indian 84–89 patients with fluoropyrimidine-related toxicity. The frequency of this variant is 0% in East Asian reference populations, 0.3% in Middle Eastern reference populations, and 0.3-1.5% in South Asian reference populations 40,41 .…”

Section: Discussionmentioning

confidence: 99%

DPYDgenetic polymorphisms in non-European patients with severe fluoropyrimidine-related toxicity: A systematic review

Chan,

Zhang,

Pirmohamed

2023

Preprint

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BackgroundPre-treatmentDPYDscreening is mandated in the UK and EU to reduce the risk of severe and potentially fatal fluoropyrimidine-related toxicity. FourDPYDgene variants which are more prominently found in Europeans are tested.MethodsOur systematic review in patients of non-European ancestry followed PRISMA guidelines to identify relevant articles up to April 2023. Publishedin silicofunctional predictions andin vitrofunctional data were also extracted. We also undertookin silicoprediction for allDPYDvariants identified.ResultsIn 32 studies, published between 1998 and 2022, 53DPYDvariants were evaluated in patients from 12 countries encompassing 5 ethnic groups: African American, East Asian, Latin American, Middle Eastern, and South Asian. One of the 4 common EuropeanDPYDvariants, c.1905+1G>A, is also present in South Asian, East Asian and Middle Eastern patients with severe fluoropyrimidine-related toxicity. There seems to be relatively strong evidence for the c.557A>G variant, which is found in individuals of African ancestry, but is not currently included in the UK genotyping panel.ConclusionExtending UK pre-treatmentDPYDscreening to include variants that are present in some non-European ancestry groups will improve patient safety and reduce race and health inequalities in ethnically diverse societies.

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“…According to the results of certain studies, a mortality rate of 0.5% and grades III-IV toxicity of 20-30% have been reported in patients treated with 5-FU for advanced cancer (17)(18)(19)(20)(21). Detection of the genetic polymorphism is thought to be a useful method for the prediction of severe toxicity and treatment outcome.…”

Section: Discussionmentioning

confidence: 99%

Association and prediction of severe 5-fluorouracil toxicity with dihydropyrimidine dehydrogenase gene polymorphisms: A meta-analysis

Leung

Chan

2015

Biomedical Reports

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Abstract. The aim of the present study was to evaluate the association and prediction of dihydropyrimidine dehydrogenase gene (DPYD) polymorphisms and the risk of 5-fluorouracil (5-FU) severe toxicity in cancer patients. A meta-analysis of the published literature was conducted to summarize evidence for DPYD gene polymorphisms associated with an increased risk of severe 5-FU toxicity in patients with cancer from an Asian population. Relevant literature was identified using the PubMed and Cochrane databases on April 11, 2014. Combined risk ratios and 95% confidence intervals (CIs) were calculated in a fixed-effects model. A total of 5 clinical studies were retrieved in the meta-analysis, including 764 cancer patients with DPYD gene polymorphisms who received 5-FU-based chemotherapy. Overall, DPYD gene polymorphisms were associated with the increased risk of 5-FU severe toxicity [risk ratio=2.54 (2.15-3.00); 95% CI, P=0.0001]. In conclusion, the present meta-analysis suggested that polymorphisms of several DPYD gene polymorphisms are associated with an increased risk of severe toxic response to 5-FU.

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Pharmacogenetic Study of 5-Fluorouracil-Related Severe Toxicity in Thai Cancer Patients: A Novel SNP Detection

Cited by 5 publications

References 23 publications

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

DPYDgenetic polymorphisms in non-European patients with severe fluoropyrimidine-related toxicity: A systematic review

Association and prediction of severe 5-fluorouracil toxicity with dihydropyrimidine dehydrogenase gene polymorphisms: A meta-analysis

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