CYP2C19 Genotype Modifies Voriconazole-Associated Cutaneous SCC Risk After Lung Transplantation

Lung transplant recipients with the ultrarapid metabolic CYP2C19*17 allele have an increased risk of squamous cell carcinoma

medwireNews: The ultrarapid metabolising allele of the cytochrome P450 2C19 (CYP2C19) gene modifies the risk of cutaneous squamous cell carcinoma (SCC) associated with any exposure to the antifungal agent voriconazole in lung transplant recipients, according to a research letter in JAMA Dermatology.

Study authors Kiyanna Williams and Sarah Arron, from the University of California–San Francisco in the USA, explain that voriconazole is commonly given to organ transplant recipients, but that it has been shown to elevate SCC risk by 73%.

Voriconazole is mainly metabolised by CYP2C19 and the primary metabolite voriconazole-N-oxide is believed to be the key DNA damaging agent. Therefore the researchers investigated the role of the CYP2C19 alleles in modifying the risk, as polymorphisms in the CYP2C19 enzyme can affect the circulating levels of voriconazole and its primary metabolites.

The study included 177 patients who had undergone lung transplantation – of these 31.1% were heterozygous for the *17 allele and 6.2% were homozygous. The presence of the *17 allele significantly increased the risk of developing SCC by 74% compared with patients not harbouring the allele.

The ultrarapid metabolising *17 allele also modified the risk of SCC associated with any exposure to voriconazole, with a decrease in risk from 91% in the univariate model to 24% in the bivariate model adjusting for genotype.

And in a multivariate analysis accounting for male gender, White ethnicity and age over 50 years at transplantation, the SCC risk associated with voriconazole exposure further reduced to 8% while the genotype-associated risk was 52%. The researchers note, however, that the study was not adequately powered for multivariate analysis.

The presence of the *17 allele did not have an impact on the SCC risk associated with cumulative voriconazole exposure. The 2% increase in the risk of developing SCC per 30-day course of voriconazole 200 mg twice daily remained unchanged after adjustment for genotype.

“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”, the investigators conclude.

Reference

Williams K, Arron ST. Association of CYP2C19 *17/*17 genotype with the risk of voriconazole-associated squamous cell carcinoma. JAMA Dermatol 2016; Advance online publication 16 March. doi: 10.1001/jamadermatol.2016.0351

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