The Prevalence of DPYD*9A (c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines: Updated Analysis

Anu Singh Maharjan, Gwendolyn A. McMillin, Girijesh Kumar Patel, Saad Awan, William R. Taylor, Sachin Pai, Arthur E Frankel, Cindy Nelson, Bin Wang, Peter Joel Hosein, Ajay P. Singh, Moh'd Khushman

Research output: Contribution to journalArticle

Abstract

Introduction: The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46%]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation. Patients and Methods: Between 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis. Results: Heterozygous and homozygous DPYD*9A genotypes were identified in 46 (41%) and 11 (10%) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53%) and 27 (47%) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9%), 26 (45.6%), and 2 (3.5%) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275). Conclusion: In our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41% and 10%, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias. In our previous study of a cohort of 28 patients, DPYD∗9A (c.85T>C) was the most commonly diagnosed variant (46%) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD∗9A variant and to confirm the genotype-phenotype correlation. In this updated analysis, the prevalence of heterozygous and homozygous DPYD∗9A genotypes were 41% and 10%, respectively; the correlation between DPYD∗9A genotype and dihydropyrimidine dehydrogenase clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.

Original languageEnglish (US)
JournalClinical Colorectal Cancer
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Dihydrouracil Dehydrogenase (NADP)
Genetic Association Studies
Genotype
Genes
Neoplasms
Selection Bias
Phenotype
Sample Size
Dihydropyrimidine Dehydrogenase Deficiency

Keywords

  • Dihydropyrimidine dehydrogenase
  • DPYD*9A (c.85T>C) variant
  • Fluoropyrimidines
  • Gastrointestinal malignancy
  • Germline pharmacogenomics

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology

Cite this

The Prevalence of DPYD*9A (c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines : Updated Analysis. / Maharjan, Anu Singh; McMillin, Gwendolyn A.; Patel, Girijesh Kumar; Awan, Saad; Taylor, William R.; Pai, Sachin; Frankel, Arthur E; Nelson, Cindy; Wang, Bin; Hosein, Peter Joel; Singh, Ajay P.; Khushman, Moh'd.

In: Clinical Colorectal Cancer, 01.01.2019.

Research output: Contribution to journalArticle

Maharjan, Anu Singh ; McMillin, Gwendolyn A. ; Patel, Girijesh Kumar ; Awan, Saad ; Taylor, William R. ; Pai, Sachin ; Frankel, Arthur E ; Nelson, Cindy ; Wang, Bin ; Hosein, Peter Joel ; Singh, Ajay P. ; Khushman, Moh'd. / The Prevalence of DPYD*9A (c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines : Updated Analysis. In: Clinical Colorectal Cancer. 2019.
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title = "The Prevalence of DPYD*9A (c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines: Updated Analysis",
abstract = "Introduction: The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46{\%}]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation. Patients and Methods: Between 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis. Results: Heterozygous and homozygous DPYD*9A genotypes were identified in 46 (41{\%}) and 11 (10{\%}) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53{\%}) and 27 (47{\%}) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9{\%}), 26 (45.6{\%}), and 2 (3.5{\%}) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275). Conclusion: In our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41{\%} and 10{\%}, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias. In our previous study of a cohort of 28 patients, DPYD∗9A (c.85T>C) was the most commonly diagnosed variant (46{\%}) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD∗9A variant and to confirm the genotype-phenotype correlation. In this updated analysis, the prevalence of heterozygous and homozygous DPYD∗9A genotypes were 41{\%} and 10{\%}, respectively; the correlation between DPYD∗9A genotype and dihydropyrimidine dehydrogenase clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.",
keywords = "Dihydropyrimidine dehydrogenase, DPYD*9A (c.85T>C) variant, Fluoropyrimidines, Gastrointestinal malignancy, Germline pharmacogenomics",
author = "Maharjan, {Anu Singh} and McMillin, {Gwendolyn A.} and Patel, {Girijesh Kumar} and Saad Awan and Taylor, {William R.} and Sachin Pai and Frankel, {Arthur E} and Cindy Nelson and Bin Wang and Hosein, {Peter Joel} and Singh, {Ajay P.} and Moh'd Khushman",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.clcc.2019.04.005",
language = "English (US)",
journal = "Clinical Colorectal Cancer",
issn = "1533-0028",
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TY - JOUR

T1 - The Prevalence of DPYD*9A (c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines

T2 - Updated Analysis

AU - Maharjan, Anu Singh

AU - McMillin, Gwendolyn A.

AU - Patel, Girijesh Kumar

AU - Awan, Saad

AU - Taylor, William R.

AU - Pai, Sachin

AU - Frankel, Arthur E

AU - Nelson, Cindy

AU - Wang, Bin

AU - Hosein, Peter Joel

AU - Singh, Ajay P.

AU - Khushman, Moh'd

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46%]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation. Patients and Methods: Between 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis. Results: Heterozygous and homozygous DPYD*9A genotypes were identified in 46 (41%) and 11 (10%) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53%) and 27 (47%) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9%), 26 (45.6%), and 2 (3.5%) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275). Conclusion: In our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41% and 10%, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias. In our previous study of a cohort of 28 patients, DPYD∗9A (c.85T>C) was the most commonly diagnosed variant (46%) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD∗9A variant and to confirm the genotype-phenotype correlation. In this updated analysis, the prevalence of heterozygous and homozygous DPYD∗9A genotypes were 41% and 10%, respectively; the correlation between DPYD∗9A genotype and dihydropyrimidine dehydrogenase clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.

AB - Introduction: The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46%]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation. Patients and Methods: Between 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis. Results: Heterozygous and homozygous DPYD*9A genotypes were identified in 46 (41%) and 11 (10%) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53%) and 27 (47%) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9%), 26 (45.6%), and 2 (3.5%) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275). Conclusion: In our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41% and 10%, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias. In our previous study of a cohort of 28 patients, DPYD∗9A (c.85T>C) was the most commonly diagnosed variant (46%) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD∗9A variant and to confirm the genotype-phenotype correlation. In this updated analysis, the prevalence of heterozygous and homozygous DPYD∗9A genotypes were 41% and 10%, respectively; the correlation between DPYD∗9A genotype and dihydropyrimidine dehydrogenase clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.

KW - Dihydropyrimidine dehydrogenase

KW - DPYD9A (c.85T>C) variant

KW - Fluoropyrimidines

KW - Gastrointestinal malignancy

KW - Germline pharmacogenomics

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U2 - 10.1016/j.clcc.2019.04.005

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