Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 6, pp 1359–1363 | Cite as

Prevalence of the DPYD variant (Y186C) in Brazilian individuals of African ancestry

  • Geraldo Felício Cunha-Junior
  • Luciana Bastos-Rodrigues
  • Pedro G. Azevedo
  • Maria Aparecida Bicalho
  • Luiz Alexandre V. Magno
  • Luiz De MarcoEmail author
  • Luiz Gonzaga Coelho
Short Communication
  • 50 Downloads

Abstract

Purpose

The presence of deleterious variants of dihydropyrimidine-dehydrogenase gene (DPYD) is associated with 5-Fluorouracil toxicity. Most of the data are based on findings in Caucasian populations. The variant Y186C (rs115232898) is found almost exclusively in African populations and is related to low DPD function. Its prevalence may vary among African subpopulations and in African Americans. There is no information in other populations. Brazil has the biggest African population outside Africa. We studied for the first time the frequency of this mutation in African Brazilians.

Methods

We amplified exon 6 of DPYD extracted from genomic DNA of 79 healthy volunteers of genetically defined African ancestry from Southeast Brazil and 36 self-reported African descendants from Northeast Brazil in order to determine the prevalence of the variant Y186C in Brazilians of African ancestry.

Results

The variant Y186C was found in heterozygosity in two samples from Southeast (2.53%) and one from Northeast (2.77%) Brazil. Overall, the prevalence of this mutation in the 115 African Brazilians was 2.6%.

Conclusions

The variant Y186C is prevalent among Brazilians of African ancestry and should be taken in account in targeted genotyping for fluoropyrimidine risk variants.

Keywords

DPYD variant Y186C 5-Fluorouracil 

Abbreviations

DPD

Dihydropyrimidine-dehydrogenase

DPYD

The gene encoding DPD

FP

Fluoropyrimidines

5FU

Fluorouracil

Notes

Funding

This work was partially funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), Brazil.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Longley DB, Harkin DP, Johnston PG (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338CrossRefGoogle Scholar
  2. 2.
    Meta-Analysis Group In Cancer, Lévy E, Piedbois P, Buyse M, Pignon JP, Rougier P, Ryan L, Hansen R, Zee B, Weinerman B, Pater J, Leichman C, Macdonald J, Benedetti J, Lokich J, Fryer J, Brufman G, Isacson R, Laplanche A, Quinaux E, Thirion P (1998) Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol 16:3537–3541CrossRefGoogle Scholar
  3. 3.
    Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M; German 5-FU Toxicity Study Group (2008) 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 26:2131–2138CrossRefGoogle Scholar
  4. 4.
    van Staveren MC, Guchelaar HJ, van Kuilenburg AB, Gelderblom H, Maring JG (2013) Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency. Pharmcogenom J 13:389–395CrossRefGoogle Scholar
  5. 5.
    Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, Largiadèr CR, Jennings BA, Marinaki AM, Sanderson JD, Kleibl Z, Kleiblova P, Schwab M, Zanger UM, Palles C, Tomlinson I, Gross E, van Kuilenburg AB, Punt CJ, Koopman M, Beijnen JH, Cats A, Schellens JH (2015) Clinical relevance of DPYD variants c.1679T > G, c.1236G > A/HapB3, and c.1601G > A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol 16:1639–1650CrossRefGoogle Scholar
  6. 6.
    Offer SM, Wegner NJ, Fossum C, Wang K, Diasio RB (2013) Phenotypic profiling of DPYD variations relevant to 5-fluorouracil sensitivity using real-time cellular analysis and in vitro measurement of enzyme activity. Cancer Res 73:1958–1968CrossRefGoogle Scholar
  7. 7.
    Nie Q, Shrestha S, Tapper EE, Trogstad-Isaacson CS, Bouchonville KJ, Lee AM, Wu R, Jerde CR, Wang Z, Kubica PA, Offer SM, Diasio RB (2017) Quantitative contribution of rs75017182 to dihydropyrimidine dehydrogenase mRNA splicing and enzyme activity. Clin Pharmacol Ther 102:662–670CrossRefGoogle Scholar
  8. 8.
    The International Genome Sample Resource (IGSR). Providing ongoing support for the 1000 Genomes Project data. Genome Browsers: 1000 Genomes data in Ensemble. 2018. Available at: <http://www.internationalgenome.org/1000-genomes-browsers>
  9. 9.
    Mattison LK, Fourie J, Desmond RA, Modak A, Saif MW, Diasio RB (2006) Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians. Clin Cancer Res 12:5491–5495CrossRefGoogle Scholar
  10. 10.
    Thomas HR, Ezzeldin HH, Guarcello V, Mattison LK, Fridley BL, Diasio RB (2007) Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism. Pharmacogenet Genom 17:973–987CrossRefGoogle Scholar
  11. 11.
    Thomas HR, Ezzeldin HH, Guarcello V, Mattison LK, Fridley BL, Diasio RB (2008) Genetic regulation of beta-ureidopropionase and its possible implication in altered uracil catabolism. Pharmacogenet Genom 18:25–35CrossRefGoogle Scholar
  12. 12.
    Offer SM, Lee AM, Mattison LK, Fossum C, Wegner NJ, Diasio RB (2013) A DPYD variant (Y186C) in individuals of African ancestry is associated with reduced DPD enzyme activity. Clin Pharmacol Ther 94:158–166CrossRefGoogle Scholar
  13. 13.
    Ezzeldin HH, Lee AM, Mattison LK, Diasio RB (2005) Methylation of the DPYD promoter: an alternative mechanism for dihydropyrimidine dehydrogenase deficiency in cancer patients. Clin Cancer Res 11(24 Pt 1):8699–8705CrossRefGoogle Scholar
  14. 14.
    Offer SM, Fossum CC, Wegner NJ, Stuflesser AJ, Butterfield GL, Diasio RB (2014) Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Cancer Res 74:2545–2554CrossRefGoogle Scholar
  15. 15.
    Offer SM, Diasio RB (2014) Response to “A case of 5-FU-related severe toxicity associated with the p.Y186C DPYD variant”. Clin Pharmacol Ther 95:137CrossRefGoogle Scholar
  16. 16.
    Saif MW, Lee AM, Offer SM, McConnell K, Relias V, Diasio RB (2014) A DPYD variant (Y186C) specific to individuals of African descent in a patient with life-threatening 5-FU toxicity potential for an individualized medicine approach. Mayo Clin Proc 89:131–136CrossRefGoogle Scholar
  17. 17.
    Zaanan A, Dumont LM, Loriot MA, Taieb J, Narjoz C (2014) A case of 5-FU-related severe toxicity associated with the p.Y186C DPYD variant. Clin Pharmacol Ther 95:136CrossRefGoogle Scholar
  18. 18.
    Elraiyah T, Jerde CR, Shrestha S, Wu R, Nie Q, Giama NH, Sarangi V, Roberts LR, Offer SM, Diasio RB (2017) Novel deleterious dihydropyrimidine dehydrogenase variants may contribute to 5-fluorouracil sensitivity in an East African population. Clin Pharmacol Ther 101:382–390CrossRefGoogle Scholar
  19. 19.
    Bastos-Rodrigues L, Pimenta J, Pena S (2006) The genetic structure of human populations studied through short insertion–deletion polymorphisms. Ann Hum Genet 70(Pt 5):658–665CrossRefGoogle Scholar
  20. 20.
    Pritchard JK, Stephens M, Donnelly P (2010) Inference of population structure using multilocus genotype data. Genetics 155:945–959Google Scholar
  21. 21.
    Tishkoff SA, Reed FA, Friedlaender FR, Ehret C, Ranciaro A, Froment A, Hirbo JB, Awomoyi AA, Bodo JM, Doumbo O, Ibrahim M, Juma AT, Kotze MJ, Lema G, Moore JH, Mortensen H, Nyambo TB, Omar SA, Powell K, Pretorius GS, Smith MW, Thera MA, Wambebe C, Weber JL, Williams SM (2009) The genetic structure and history of Africans and African Americans. Science 324:1035–1044CrossRefGoogle Scholar
  22. 22.
    Patin E, Lopez M, Grollemund R, Verdu P, Harmant C, Quach H, Laval G, Perry GH, Barreiro LB, Froment A, Heyer E, Massougbodji A, Fortes-Lima C, Migot-Nabias F, Bellis G, Dugoujon JM, Pereira JB, Fernandes V, Pereira L, Van der Veen L, Mouguiama-Daouda P, Bustamante CD, Hombert JM, Quintana-Murci L (2017) Dispersals and genetic adaptation of Bantu-speaking populations in Africa and North America. Science 356:543–546CrossRefGoogle Scholar
  23. 23.
    Cunha-Junior GF, De Marco L, Bastos-Rodrigues L, Bolina MB, Martins FL, Pianetti GA, Cesar IC, Coelho LG (2013) (13)C-uracil breath test to predict 5-fluorouracil toxicity in gastrointestinal cancer patients. Cancer Chemother Pharmacol 72:1273–1282CrossRefGoogle Scholar
  24. 24.
    Galarza AF, Linden R, Antunes MV, Hahn RZ, Raymundo S, da Silva AC, Staggemeier R, Spilki FR, Schwartsmann G (2016) Endogenous plasma and salivary uracil to dihydrouracil ratios and DPYD genotyping as predictors of severe fluoropyrimidine toxicity in patients with gastrointestinal malignancies. Clin Biochem 49:1221–1226CrossRefGoogle Scholar
  25. 25.
    Klein HS (2002) Homo brasilis: Aspectos Genéticos, Lingüísticos. Históricos e Socioantropológicos da Formação do Povo Brasileiro, FUNPEC-RP, Ribeirão Preto, BrasilGoogle Scholar
  26. 26.
    Kehdy FS, Gouveia MH, Machado M, Magalhães WC, Horimoto AR, Horta BL, Moreira RG, Leal TP, Scliar MO, Soares-Souza GB, Rodrigues-Soares F, Araújo GS, Zamudio R, Sant Anna HP, Santos HC, Duarte NE, Fiaccone RL, Figueiredo CA, Silva TM, Costa GN, Beleza S, Berg DE, Cabrera L, Debortoli G, Duarte D, Ghirotto S, Gilman RH, Gonçalves VF, Marrero AR, Muniz YC, Weissensteiner H, Yeager M, Rodrigues LC, Barreto ML, Lima-Costa MF, Pereira AC, Rodrigues MR, Tarazona-Santos E; Brazilian EPIGEN Project Consortium (2015) Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations. Proc Natl Acad Sci USA 112:8696–8701CrossRefGoogle Scholar
  27. 27.
    Lima-Costa MF, Rodrigues LC, Barreto ML, Gouveia M, Horta BL, Mambrini J, Kehdy FS, Pereira A, Rodrigues-Soares F, Victora CG, Tarazona-Santos E, Epigen-Brazil Group (2015) Genomic ancestry and ethnoracial self-classification based on 5,871 community-dwelling Brazilians (The Epigen Initiative). Sci Rep 5:9812–9818CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Geraldo Felício Cunha-Junior
    • 1
    • 2
  • Luciana Bastos-Rodrigues
    • 3
    • 5
  • Pedro G. Azevedo
    • 5
  • Maria Aparecida Bicalho
    • 1
    • 5
  • Luiz Alexandre V. Magno
    • 5
  • Luiz De Marco
    • 4
    • 5
    Email author
  • Luiz Gonzaga Coelho
    • 1
  1. 1.Department of Internal MedicineUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Department of OncologyHospital da Baleia, Fundação Benjamim GuimarãesBelo HorizonteBrazil
  3. 3.Department of NutritionUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  4. 4.Department of SurgeryFederal University of Minas GeraisBelo HorizonteBrazil
  5. 5.Molecular Medicine Technology CenterUniversidade Federal de Minas GeraisBelo HorizonteBrazil

Personalised recommendations