A DPYD Variant (Y186C) in Individuals of African Ancestry is Associated with Reduced DPD Enzyme Activity

Overview

Journal Clin Pharmacol Ther

Publisher Wiley

Specialty Pharmacology

Date 2013 Apr 17

PMID 23588312

Citations 46

Authors

S M Offer

A M Lee

L K Mattison

C Fossum

N J Wegner

R B Diasio

Affiliations

Soon will be listed here.

Abstract

5-Fluorouracil (5-FU) is used to treat many aggressive cancers, such as those of the colon, breast, and head and neck. The responses to 5-FU, with respect to both toxicity and efficacy, vary among racial groups, potentially because of variability in the activity levels of the enzyme dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene). In this study, the genetic associations between DPYD variations and circulating mononuclear-cell DPD enzyme activity were evaluated in 94 African-American and 81 European-American volunteers. The DPYD-Y186C variant was unique to individuals of African ancestry, and DPD activity was 46% lower in carriers as compared with noncarriers (279 ± 35 vs. 514 ± 168 pmol 5-FU min(-1) mg(-1); P = 0.00029). In this study, 26% of the African Americans with reduced DPD activity were carriers of Y186C. In the African-American cohort, after excluding Y186C carriers, homozygous carriers of C29R showed 27% higher DPD activity as compared with noncarriers (609 ± 152 and 480 ± 152 pmol 5-FU min(-1) mg(-1), respectively; P = 0.013).

Citing Articles

Dihydropyrimidine Dehydrogenase Deficiency (DPYD) Genotyping-Guided Fluoropyrimidine-Based Adjuvant Chemotherapy for Breast Cancer. A Cost-Effectiveness Analysis.

Abushanab D, Mohamed S, Abdel-Latif R, Moustafa D, Marridi W, Elazzazy S Clin Drug Investig. 2025; 45(3):151-163.

PMID: 39885055 PMC: 11876264. DOI: 10.1007/s40261-024-01413-8.

The Frequency of c.557A>G in the Dominican Population and Its Association with African Ancestry.

Guevara M, de la Cruz C, Rodrigues-Soares F, Rodriguez E, Manochio C, Penas-Lledo E Pharmaceutics. 2025; 17(1).

PMID: 39861660 PMC: 11768636. DOI: 10.3390/pharmaceutics17010008.

Strategies for DPYD testing prior to fluoropyrimidine chemotherapy in the US.

Tracksdorf T, Smith D, Pearse S, Cicali E, Aquilante C, Scott S Support Care Cancer. 2024; 32(8):497.

PMID: 38980476 DOI: 10.1007/s00520-024-08674-1.

Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase () Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.

Nguyen D, Morris S, Hamilton A, Kwange S, Steuerwald N, Symanowski J JCO Precis Oncol. 2024; 8:e2300623.

PMID: 38935897 PMC: 11371106. DOI: 10.1200/PO.23.00623.

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

Chan T, Zhang J, Pirmohamed M Br J Cancer. 2024; 131(3):498-514.

PMID: 38886557 PMC: 11300675. DOI: 10.1038/s41416-024-02754-z.

References

Schwab M, Zanger U, Marx C, Schaeffeler E, Klein K, Dippon J . Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol. 2008; 26(13):2131-8. DOI: 10.1200/JCO.2006.10.4182. View

Han H, Reis I, Zhao W, Kuroi K, Toi M, Suzuki E . Racial differences in acute toxicities of neoadjuvant or adjuvant chemotherapy in patients with early-stage breast cancer. Eur J Cancer. 2011; 47(17):2537-45. DOI: 10.1016/j.ejca.2011.06.027. View

Morsman J, Sludden J, Ameyaw M, Githanga J, Indalo A, Ofori-Adjei D . Evaluation of dihydropyrimidine dehydrogenase activity in South-west Asian, Kenyan and Ghanaian populations. Br J Clin Pharmacol. 2000; 50(3):269-72. PMC: 2014976. DOI: 10.1046/j.1365-2125.2000.00242.x. View

Swen J, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee A, Mulder H . Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011; 89(5):662-73. DOI: 10.1038/clpt.2011.34. View

Peltonen L, Altshuler D, de Bakker P, Deloukas P, Gabriel S, Gwilliam R . Integrating common and rare genetic variation in diverse human populations. Nature. 2010; 467(7311):52-8. PMC: 3173859. DOI: 10.1038/nature09298. View

Harris B, Song R, Soong S, Diasio R . Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous.... Cancer Res. 1990; 50(1):197-201. View

Laurie J, MOERTEL C, Fleming T, Wieand H, Leigh J, Rubin J . Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol. 1989; 7(10):1447-56. DOI: 10.1200/JCO.1989.7.10.1447. View

Harris B, Carpenter J, Diasio R . Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer. 1991; 68(3):499-501. DOI: 10.1002/1097-0142(19910801)68:3<499::aid-cncr2820680309>3.0.co;2-f. View

Seck K, Riemer S, Kates R, Ullrich T, Lutz V, Harbeck N . Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals. Clin Cancer Res. 2005; 11(16):5886-92. DOI: 10.1158/1078-0432.CCR-04-1784. View

10.

Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T . Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004; 350(23):2343-51. DOI: 10.1056/NEJMoa032709. View

11.

Longley D, Harkin D, Johnston P . 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003; 3(5):330-8. DOI: 10.1038/nrc1074. View

12.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

13.

Jessup J, Stewart A, Greene F, Minsky B . Adjuvant chemotherapy for stage III colon cancer: implications of race/ethnicity, age, and differentiation. JAMA. 2005; 294(21):2703-11. DOI: 10.1001/jama.294.21.2703. View

14.

Ezzeldin H, Lee A, Mattison L, Diasio R . Methylation of the DPYD promoter: an alternative mechanism for dihydropyrimidine dehydrogenase deficiency in cancer patients. Clin Cancer Res. 2005; 11(24 Pt 1):8699-705. DOI: 10.1158/1078-0432.CCR-05-1520. View

15.

Sanoff H, Sargent D, Green E, McLeod H, Goldberg R . Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial. J Clin Oncol. 2009; 27(25):4109-15. PMC: 2734422. DOI: 10.1200/JCO.2009.21.9527. View

16.

David McCollum A, Catalano P, Haller D, Mayer R, Macdonald J, Benson 3rd A . Outcomes and toxicity in african-american and caucasian patients in a randomized adjuvant chemotherapy trial for colon cancer. J Natl Cancer Inst. 2002; 94(15):1160-7. DOI: 10.1093/jnci/94.15.1160. View

17.

Sugihara K, Ohtsu A, Shimada Y, Mizunuma N, Lee P, De Gramont A . Safety analysis of FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies. Clin Colorectal Cancer. 2011; 11(2):127-37. PMC: 4127629. DOI: 10.1016/j.clcc.2011.09.001. View

18.

de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J . Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000; 18(16):2938-47. DOI: 10.1200/JCO.2000.18.16.2938. View

19.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

20.

Diasio R, Beavers T, Carpenter J . Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest. 1988; 81(1):47-51. PMC: 442471. DOI: 10.1172/JCI113308. View