Fluoropyrimidine-Induced Severe Toxicities Associated with Rare DPYD Polymorphisms: Case Series from Saudi Arabia and a Review of the Literature

Bukhari, Nedal; Alshangiti, Abdulraheem; Tashkandi, Emad; Algarni, Mohammed; Al-Shamsi, Humaid O.; Al‐Khallaf, Hamoud

doi:10.3390/clinpract11030062

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…13 DPYD variants (1 splice donor, 8 missense, 4 intronic) were reported in patients of Middle Eastern ancestry. There were 2 cohort studies from Tunisia 79,80 , 1 cohort study from Jordan 81 1 case report from Lebanon 82 and 1 case series from Saudi Arabia 83 (Supplementary Table 5). None of the variants passed our filtering process (Supplementary Results).…”

Section: Resultsmentioning

confidence: 99%

“…Clearly, there are other variants in these ethnic groups which need further investigation. For example, in South Asians and Middle Easterners, our systematic review identified single occurrence of missense variants c.704G>A (p.Arg235Gln, rs755416212) 90 and c.257C>T (p.Pro86Leu, rs568132506) 83 , respectively. These variants are not reported in the CPIC guideline but are predicted to be deleterious by >80% of the in silico tools we used, with one research study reporting significant reduction of DPD activity in vitro with the c.257C>T variant 42 .…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Chan,

Zhang,

Pirmohamed

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Clearly, there are other variants in these ethnic groups which need further investigation. For example, in South Asians and Middle Easterners, our systematic review identified single occurrence of missense variants c.704G>A (p.Arg235Gln, rs755416212) [91] and c.257C>T (p.Pro86Leu, rs568132506) [84], respectively. These variants are not reported in the CPIC guideline but are predicted to be deleterious by 100% of the in silico tools we used, with one research study reporting significant reduction of DPD activity in vitro (97% decrease) with the c.257C>T variant [42].…”

Section: Discussionmentioning

confidence: 99%

“…13 DPYD variants (1 splice donor, 8 missense, 4 intronic) were reported in patients of Middle Eastern ancestry. There were 2 cohort studies from Tunisia [80,81], 1 cohort study from Jordan [82], 1 case report from Lebanon [83], and 1 case series from Saudi Arabia [84] (Supplementary Table 5). None of the variants passed our filtering process (Supplementary Results).…”

Section: Dpyd Genetic Variants Haplotypes and In Silico Predictionsmentioning

confidence: 99%

DPYD genetic polymorphisms in non-European patients with severe fluoropyrimidine-related toxicity: a systematic review

Chan,

Zhang,

Pirmohamed

2024

Br J Cancer

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Background Pre-treatment DPYD screening is mandated in the UK and EU to reduce the risk of severe and potentially fatal fluoropyrimidine-related toxicity. Four DPYD gene variants which are more prominently found in Europeans are tested. Methods Our systematic review in patients of non-European ancestry followed PRISMA guidelines to identify relevant articles up to April 2023. Published in silico functional predictions and in vitro functional data were also extracted. We also undertook in silico prediction for all DPYD variants identified. Results In 32 studies, published between 1998 and 2022, 53 DPYD variants 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 European DPYD variants, 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. Conclusion Extending UK pre-treatment DPYD screening 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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“…DPD metabolizes over 80% of 5-FU in the liver. The conversion of 5-FU to inactive dihydrofluorouracil (DHFU) occurs through the DPD enzyme [6][7][8]. TYMS is the enzyme that converts deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), which is critical for DNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

Thymidylate Synthase (TYMS) and Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms Associated With Severe Capecitabine Toxicity: The First Case From Saudi Arabia

Bukhari,

Al-Mohanna,

Almsned

2023

Cureus

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Dihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of fluoropyrimidine chemotherapy. Deficiencies in this enzyme level typically predispose patients to fluoropyrimidine toxicities, and they are often linked to DPYD gene polymorphisms. Other gene polymorphisms such as thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR) may induce similar toxicities. We report a patient with resected stage III colon cancer presenting with severe toxicity to adjuvant capecitabine, a prodrug of 5-fluorouracil (5-FU). Her DPYD gene sequencing was normal. However, the patient was heterozygous for c.1298A>C (p.E429A) in the methylenetetrahydrofolate reductase (MTHFR) gene and c.*450_*455del in the thymidylate synthase (TYMS) gene. The capecitabine dose was reduced in subsequent treatments and then titrated up gradually with no major side effects reported.

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Fluoropyrimidine-Induced Severe Toxicities Associated with Rare DPYD Polymorphisms: Case Series from Saudi Arabia and a Review of the Literature

Cited by 6 publications

References 19 publications

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

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

DPYD genetic polymorphisms in non-European patients with severe fluoropyrimidine-related toxicity: a systematic review

Thymidylate Synthase (TYMS) and Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms Associated With Severe Capecitabine Toxicity: The First Case From Saudi Arabia

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