Pharmacogenetic phenomena, as pointed out previously, need not be restricted to the observation of a direct association between allelic sequence variation and phenotype, but may extend to a broad variety of indirect manifestations of underlying, but often (as yet) unrecognized sequence variation. Thus, differential methylation of the promoter region of O6-methylguanine DNA methylase has recently been reported to be associated with differential efficacy of chemotherapy with alkylating agents. If methylation is present, expression of the enzyme that rapidly reverses alkylation and induces drug resistance is inhibited, and therapeutic efficacy is greatly enhanced.21
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