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The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors’ articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G > A) from TPMT*24 to TPMT*30 and position 611 (T > C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.

The aim of a PharmGKB VIP summary is to provide a simple overview of a gene with respect to drug effects. In some cases, there may be extensive evidence of variants that have known pharmacogenomic relevance, whereas in other cases, the summary may serve to highlight the gaps in knowledge where further study would aid the field. This summary points to the PharmGKB website to provide an interactive version that is linked to annotated publications and to related drugs, diseases, and pathways. The human CYP3A subfamily, CYP3A4, CYP3A5, CYP3A7, and CYP3A43, is one of the most versatile of the biotransformation systems that facilitate the elimination of drugs (37% of the 200 most frequently prescribed drugs in the US [1]). Together, CYP3A4 and CYP3A5 account for ~30% of hepatic cytochrome P450, and approximately half of the medications that are oxidatively metabolized by P450 are CYP3A substrates. Both CYP3A4 and CYP3A5 are expressed in the liver and intestine, with CYP3A5 being the predominant form expressed in extrahepatic tissues. The CYP3A5 cDNA sequence was first described independently by Aoyama et al. [2] and Schuetz et al. [3]. The CYP3A5 gene is located on chromosome 7q22.1 along with other CYP3A family members. The gene is on the minus chromosomal strand, consists of nine exons, and encodes a 502-amino-acid protein.

Thiopurine S-methyltransferase (TPMT, S-adenosyl-L-methionine : thiopurine S-methyltransferase; EC 2.1.1.67) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and azathioprine as well as other aromatic and heterocyclic sulfhydryl compounds [1,2].Weinshilboum and Sladek

Epidermal growth factor receptor (EGFR) encodes a transmembrane glycoprotein. This protein is a member of the protein kinase superfamily, which consists of EGFR (ErbB1/HER1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). All family members contain an extracellular ligand-binding domain, a single membrane-spanning region, a juxtamembrane nuclear localization signal, and a cytoplasmic tyrosine kinase domain. They are collectively called HER receptors and are ubiquitously expressed in various cell types, primarily in those of epithelial, mesenchymal and neuronal origin. Under homeostatic conditions, receptor activation is tightly regulated by the availability of ligands, which together form the epidermal growth factor (EGF) family [1]. From those ligands, EGF, transforming growth factor alpha and amphiregulin bind specifically to EGFR [2]. Binding of the EGFR or other family members to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. The EGFR involvement in carcinogenesis has been well established and mutations in EGFR can be utilized as predictive markers in the treatment of cancer. In this review, we will focus on the effects of genetic variants (somatic and germline) in the treatment of non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKI) and will provide a pharmacogenomics overview of EGFR in humans. This Very Important Pharmacogene (VIP) summary is available with interactive links to gene variants and drugs on the PharmGKB website http://pharmgkb.org/gene/PA7360 [3].