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Table 1.
Distribution of CYP2C19 Genotypes in the Cohorta

a*1 is the wild-type allele, *17 is rapid metabolizing, *2 and *3 are nonfunctional.

Table 2.
Association Between the *17 Allele and Risk for Squamous Cell Carcinoma

Abbreviation: HR, hazard ratio.

aPatients with 1 or 2 *17 alleles are compared with the *17-negative reference population (dominant inheritance model).

bCumulative voriconazole dose measured per 30 days of 200 mg twice daily dosing.

cBivariate models are adjusted for genotype and voriconazole exposure (any or cumulative).

dAdjusted models are adjusted for male sex, white race, and age greater than 50 years at transplantation.

1.
Organ Procurement and Transplantation Network. OPTN Database: view data reports. https://optn.transplant.hrsa.gov/data/view-data-reports/. Accessed March 8, 2016.
2.
Mansh  M, Binstock  M, Williams  K,  et al.  Voriconazole exposure and risk of cutaneous squamous cell carcinoma, Aspergillus colonization, invasive aspergillosis and death in lung transplant recipients.  Am J Transpl. 2016;16(1):262-270.PubMedGoogle ScholarCrossref
3.
Mikus  G, Scholz  IM, Weiss  J.  Pharmacogenomics of the triazole antifungal agent voriconazole.  Pharmacogenomics. 2011;12(6):861-872.PubMedGoogle ScholarCrossref
4.
Murayama  N, Imai  N, Nakane  T, Shimizu  M, Yamazaki  H.  Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes.  Biochem Pharmacol. 2007;73(12):2020-2026.PubMedGoogle ScholarCrossref
5.
Wang  G, Lei  HP, Li  Z,  et al.  The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers.  Eur J Clin Pharmacol. 2009;65(3):281-285.PubMedGoogle ScholarCrossref
6.
Williams  K, Mansh  M, Chin-Hong  P, Singer  J, Arron  ST.  Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients.  Clin Infect Dis. 2014;58(7):997-1002.PubMedGoogle ScholarCrossref
Research Letter
June 2016

Association of CYP2C19 *17/*17 Genotype With the Risk of Voriconazole-Associated Squamous Cell Carcinoma

Author Affiliations
  • 1Medical student at University of California, San Francisco, School of Medicine
  • 2Department of Dermatology, University of California, San Francisco
JAMA Dermatol. 2016;152(6):719-720. doi:10.1001/jamadermatol.2016.0351

An estimated 25 767 solid-organ transplantations were performed in 2015.1 Voriconazole, an antifungal used in organ transplant recipients, is associated with a 73% increased risk for cutaneous squamous cell carcinoma (SCC) development in lung transplant recipients (LTRs).2 The mechanism of voriconazole-associated cutaneous malignant neoplasm development is unknown, but the primary metabolite of voriconazole, voriconazole-N-oxide (VNO), is a chromophore for UVB and may play a key role in DNA damage resulting in SCC. Voriconazole is primarily metabolized into VNO by cytochrome P450 enzymes, predominantly CYP2C19 (2-4). Polymorphisms in CYP2C19 affect circulating levels of voriconazole and VNO, with poor metabolizers having 3 to 4 times higher voriconazole plasma concentrations and greater voriconazole to VNO ratios.3-5 The ultrarapid-metabolizing *17 allele of CYP2C19 (OMIM 124020), which is common in Europeans and Africans and rare in Asians, results in higher circulating concentrations of VNO. We hypothesized that LTRs with the *17 allele would have an increased risk for voriconazole-associated SCC.

Methods

The University of California, San Francisco (UCSF) Committee on Human Research approved this study. All participants gave written informed consent. This cohort was nested in a previously described cohort investigating SCC in LTRs.2 Genomic DNA and outcome data were available on 177 patients. Patients were genotyped through a polymerase chain reaction–based assay for allelic variants of the CYP2C19 enzyme, *1 (wild type), *17 (ultrarapid), and *2-*3 (nonfunctional). We assumed a dominant model for *17 activity in which patients with either 1 or 2 *17 alleles were compared with the baseline population of participants who did not carry any *17 alleles. We used Cox proportional hazard models to assess the effect of genotype and drug exposure on the hazard of SCC as described previously.2 A bivariate model was constructed including *17/*17 genotype and exposure to voriconazole considered as a time-varying covariate.2 Multivariate models were constructed using sex, age, and white race as described in Mansh et al.2

Results

Of the 177 patients, 85 (48.0%) were female, 92 (52.0%) male, 137 (77.4%) were white, and 40 (22.6%) nonwhite. Genotype distributions are presented in Table 1. Patients with the *17 allele had 74% increased hazard for SCC (95% CI, 1.06-2.84; P = .03) (Table 2). The *17 allele was a modifier for SCC risk associated with any exposure to voriconazole: in a bivariate model the hazard for SCC associated with genotype was maintained, but the hazard associated with voriconazole exposure was reduced from 1.91 (95% CI, 1.11-3.27) to 1.24 (95% CI, 0.57-2.69). This study was underpowered for adjustment for male sex, white race, and age older than 50 years at transplantation, but there was a 52% increased hazard for SCC associated with presence of the *17 allele; the voriconazole exposure hazard was reduced to 1.08 (95% CI, 0.49-2.40). Power calculations suggest that a cohort size of 575 patients would be needed to achieve a power of 0.80 in the multivariate model.

In contrast, presence of the *17 allele did not seem to modify the SCC risk associated with cumulative voriconazole dose exposure. The previously reported 2% increased hazard for SCC associated with each 30-day course of voriconazole at 200 mg twice daily did not change when adjusted for presence of the *17 allele. The univariate association of genotype with SCC risk was reduced from 1.74 to 1.61 (95% CI, 0.99-2.61) in the bivariate model and further to 1.31 (95% CI, 0.79-2.17) in the fully adjusted model.

Discussion

Retrospective cohort and case-control studies have demonstrated that voriconazole use increases the risk for developing SCC in LTRs.2,6 Our findings suggest that the ultrarapid metabolic CYP2C19 *17 allele is associated with SCC risk and modifies the association between exposure to voriconazole and SCC. Further studies with a larger sample size are required to investigate whether these findings are statistically significant for cumulative dose exposure and in models adjusted for additional SCC risk factors including sex, race, and age at transplantation.

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Article Information

Accepted for Publication: February 3, 2016.

Corresponding Author: Sarah T. Arron, MD, PhD, Department of Dermatology, University of California–San Francisco, 1701 Divisadero St, 3rd Floor, San Francisco, CA 94115 (sarah.arron@ucsf.edu).

Published Online: March 16, 2016. doi:10.1001/jamadermatol.2016.0351.

Author Contributions: Both authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Arron.

Acquisition, analysis, or interpretation of data: Both authors.

Drafting of the manuscript: Williams.

Critical revision of the manuscript for important intellectual content: Arron.

Statistical analysis: Arron.

Obtained funding: Arron.

Administrative, technical, or material support: Williams.

Study supervision: Arron.

Conflict of Interest Disclosures: Dr Arron has received research funding from Allergan, Anacor, UBC, Genentech, and Endpoint Outcomes and has been a consultant for Portola Pharmaceuticals and Gerson Lehrman Group, all unrelated to this study. No other disclosures are reported.

Funding/Support: This study was supported in part by the UCSF Nina Ireland Lung Disease Program.

Role of the Funder/Sponsor: The UCSF Nina Ireland Lung Disease Program had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We are indebted to Maxwell Binstock for his work on the UCSF Transplant Cohort. He received no compensation for his contributions beyond that received in the normal course of his employment.

References
References
1.
Organ Procurement and Transplantation Network. OPTN Database: view data reports. https://optn.transplant.hrsa.gov/data/view-data-reports/. Accessed March 8, 2016.
2.
Mansh  M, Binstock  M, Williams  K,  et al.  Voriconazole exposure and risk of cutaneous squamous cell carcinoma, Aspergillus colonization, invasive aspergillosis and death in lung transplant recipients.  Am J Transpl. 2016;16(1):262-270.PubMedGoogle ScholarCrossref
3.
Mikus  G, Scholz  IM, Weiss  J.  Pharmacogenomics of the triazole antifungal agent voriconazole.  Pharmacogenomics. 2011;12(6):861-872.PubMedGoogle ScholarCrossref
4.
Murayama  N, Imai  N, Nakane  T, Shimizu  M, Yamazaki  H.  Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes.  Biochem Pharmacol. 2007;73(12):2020-2026.PubMedGoogle ScholarCrossref
5.
Wang  G, Lei  HP, Li  Z,  et al.  The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers.  Eur J Clin Pharmacol. 2009;65(3):281-285.PubMedGoogle ScholarCrossref
6.
Williams  K, Mansh  M, Chin-Hong  P, Singer  J, Arron  ST.  Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients.  Clin Infect Dis. 2014;58(7):997-1002.PubMedGoogle ScholarCrossref
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