| BRAF gene | BRAF V600E mutation | 40–60% of advanced melanomas | Vemurafenib (Zelboraf) | Activating mutations in BRAF (a serine–threonine protein kinase) are present in 40–60% of advanced melanomas. Most (80–90%) of the mutations are the substitution of glutamic acid for valine at amino acid 600 (V600E mutation). This mutation is associated with a more aggressive clinical course. Vemurafenib, a potent inhibitor of the mutant BRAF, has a high level of therapeutic activity against advanced melanomas containing the V600E mutation. |
| Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) | CFTR G551D (defective) | CFTR G551D is present in about 4% of patients with cystic fibrosis (CF) | Ivacaftor (Kalydeco) | CFTR protein forms a channel that allows chloride ions to cross the membrane. In CF patients with the CFTR G551D mutation, the channel fails to open. Ivacaftor corrects the effects of this mutation and is approved for persons with CF age > 6 years who have at least one copy of the G551D mutation. |
| Cytochrome P450 (CYP) 2C9 variants | 2C9*2 (430C >T, ↓); 2C9*3 (1075A > C, ↓↓) | 2C9*2 and 2C9*3 are present in 9–20% of Whites, 1–3% of Blacks, and < 1% of Asians | Warfarin (Coumadin) | Hepatic CYP2C9 is responsible for the metabolic inactivation and clearance of the anticoagulant warfarin. Patients carrying 2C9*2 or 2C9*3 (or both) (heterozygote, homozygote or compound heterozygote) require a reduced warfarin maintenance dose to reach a therapeutic INR. While INR remains the standard for monitoring warfarin therapy, CYP2C9 genotyping can be an important aid to the dosing strategy for warfarin-naïve patients, particularly whites. |
| CYP 2C19 variants | 2C19*2(681G >A, none); 2C19*3(636G >A, none); 2C19*4(1A>G, none); 2C19*5(1297C >T, none) | The mutant variants are present in 12–25% of Asians, and 2–7% of Whites and Blacks | Clopidogrel (Plavix) | Clopidogrel, an antiplatelet drug, must be metabolized in the liver by CYP isoenzymes, principally CYP 2C19, to become active. When treated with clopidogrel at recommended dosages, patients with CYP 2C19 variants have more cardiovascular events than do patients with normal CYP 2C19 function. Alternative drug or intervention strategies should be considered for patients with 2C19 variants. CYP 2C19*17 carrier status (25% of Whites) is associated with increased enzyme activity and an increased risk of bleeding. |
| CYP 2D6 variants | 2D6*1 (fully functional “wild-type”) 2D6*2 (2850C>T or 4180G>C; normal function variant) 2D6*3 (2549delA with or without 1749A>G), 2D6*4 (1846G>A, with or without 1858C>T, 2938C>T or 3877G>C), 2D6*5 (whole gene deletion) and 2D6*6 (1707delT) (nonfunctioning variants) 2D6*9 (1615-2617delAAG), 2D6*10 (100C>T) and 2D6*17 (1023C>T, 2850C>T) (partially functioning variants) | 1–2% of general population carry more than 2 copies of functional alleles (eg, *1/*1×N or *1/*2×N) and are phenotypically ultrarapid metabolizers 5–10% of general population carry no functional alleles (eg, *4/*4, *4/*5, *5/*5 or *4/*6) and are phenotypically poor metabolizers | Codeine, Nortriptyline (Pamelor) | Both codeine and nortriptyline are metabolized by CYP2D6. Codeine is a prodrug and needs to be metabolized by CYP2D6, primarily to morphine, whereas nortriptyline is the active moiety and its metabolism results in inactivation of the drug. At conventional doses, those who are poor metabolizers based upon CYP2D6 genotype will derive no therapeutic benefit from codeine, but may be “overdosed” with nortriptyline and at increased risk of side effects. Conversely, at conventional doses of codeine, those who are ultrarapid metabolizers have higher than expected morphine levels (an initial “overdose”), with more side effects and a shorter than expected duration of pain control. On the other hand, patients may derive no therapeutic benefit from nortriptyline because of excessive metabolism of the drug. |
| CYP 3A5 variants | 3A5*1 (functional allele) 3A5*3 (6986A>G) (present in 82-95% Whites, 33% Blacks, 65-85% Asians) (nonfunctional allele) 3A5*6 (14690G>A) (7-17% Blacks) and 3A5*7 (27131-27132ins T) (8% Blacks) (nonfunctional alleles) | Individual carrying two functional *1 alleles (*1/*1) is extensive or rapid metabolizer Individual carrying one *1 allele and one nonfunctional allele (eg, *1/*3, *1/*6, *1/*7) is intermediate metabolizer Individual carrying two nonfunctional alleles (*3/*3, etc.) is poor metabolizer | Tacrolimus (Prograf) | Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals carrying one or two functional alleles have decreased dose-adjusted trough levels of tacrolimus compared with those who carry only nonfunctional alleles. Accordingly, an increase of standard starting dose of 1.5–2× usual dose is needed for intermediate and rapid metabolizers. |
| Dihydropyrimidine dehydrogenase (DPD) variants | DPYD*2A (1905+1G>A, none) DPYD*13 (1679T>G, ↓↓) DPYD rs67376798 (2846A>T, ↓↓) | These nonfunctional variants are present in 0.1–1% of Whites (eg, French Caucasians) | 5-Fluorouracil (5-FU), capecitabine (Xeloda) | Fluoropyrimidines (ie, 5-fluorouracil, capecitabine) are metabolized by the dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by the DPYD gene. To avoid severe or even fatal drug toxicity, an alternative drug should be selected for patients who are homozygous for DPYD nonfunctional variants (*2A, *13, or rs67376798). Consider a 50% reduction in starting dose for heterozygous patients who have low DPD activity (30–70% of normal). |
| Epidermal growth factor receptor (EGFR) (also known as HER1 or erbB-1) | Activating mutation(s) in EGFR kinase (eg, S768I, L858R, L861Q, G719X, exon 19 deletions) | Mutations in the EGFR gene are observed in about 15% of non–small cell lung cancer (NSCLC) adenocarcinoma in the United States. In Asian populations, the incidence of EGFR mutations is much higher (22–62%) | EGFR tyrosine kinase inhibitors [gefitinib (Iressa), erlotinib (Terceva), afatinib (Gilotrif), osimertinib (Tagrisso)] | Advanced NSCLC that is positive for activating EGFR mutation(s) is sensitive to EGFR-targeted tyrosine kinase inhibitors (TKI). Analysis for the presence or absence of an activating mutation in EGFR is the standard approach to decide whether to use an EGFR TKI for the initial treatment of a patient with advanced NSCLC. Note that amplification of EGFR gene or EGFR overexpression by immunohistochemistry does not predict improved outcomes with EGFR TKI. |
| HER2 | HER2 gene amplification | HER2 gene amplification is present in about 20% of breast cancers | Trastuzumab (Herceptin) | Patients with HER2 gene amplification are candidates for treatment with the drug Herceptin. Patients without HER2 amplification will not benefit from adjuvant Herceptin treatment. FISH with labeled DNA probes to the pericentromeric region of chromosome 17 and to the HER2 locus is used to determine if a patient’s breast cancer has HER2 gene amplification. Immunohistochemical stains are also used to determine if the tumor exhibits HER2 protein overexpression. |
| HLA-B*1502 allele | HLA-B*1502 | 10–15% of Asians; 1–2% of Whites | Carbamazepine (Tegretol, Epitol) | Carbamazepine is associated with serious or even fatal idiosyncratic skin reactions, eg, Stevens-Johnson syndrome and toxic epidermal necrolysis. The reactions are significantly more common in patients who carry the HLA-B*1502 allele. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. HLA-B*1502 genotyping may be useful for risk stratification in patients of Asian descent. Patients carrying the HLA-B*1502 allele should not be given carbamazepine unless the expected benefit clearly outweighs the increased risk of serious skin reactions. |
| HLA-B*5701 allele | HLA-B*5701 | 6–8% of Whites and selected Asian Indians; 1–2% of Blacks and Asians | Abacavir (Ziagen) | Abacavir is a nucleoside analog reverse transcriptase inhibitor used for HIV treatment. The major treatment-limiting toxicity for abacavir use is drug hypersensitivity, occurring in 5–8% of recipients within 6 weeks of commencing therapy. There is an established association between carriage of the HLA-B*5701 allele and abacavir hypersensitivity reactions. HLA-B*5701-positive patients should not be prescribed abacavir or an abacavir-containing regimen. |
| HLA-B*5801 allele | HLA-B*5801 | 6–8% among Southeast Asians; < 1% in Western Europeans | Allopurinol (Zyloprim) | The urate-lowering drug allopurinol can produce rare but severe hypersensitivity reactions (eg, toxic epidermal necrolysis and Stevens-Johnson syndrome), which are strongly associated with HLA-B*5801 alleles. Patients of Korean, Han Chinese, Japanese, or Thai origin should be screened for HLA-B*5801 allele, and if present, an alternative drug therapy is needed. |
| IDH2 (isocitrate dehydrogenase-2) | IDH2 mutations (R140Q, R140L, R140G, R140W, R172K, R172M, R172G, R172S, and R172W) | 15–20% acute myeloid leukemia (AML); 4–5% chronic myeloid neoplasms (MDS, MPN) | Enasidenib (Idhifa) | IDH2 mutation perturbs DNA and histone methylation in hematopoietic stem cells through production of an abnormal metabolite, 2-hydroxyglutarate (2-HG). Enasidenib is a specific inhibitor of mutant IDH2, and is indicated for the treatment of patients with relapsed or refractory acute myeloid leukemia with an IDH mutation. |
| K-ras gene | K-ras mutations (in codons 12 and 13) | 30–40% of colorectal cancer (CRC); 20–25% of non-small cell lung cancer (NSCLC) | For CRC: Cetuximab (Erbitux), Panitumumab (Vectibix) For NSCLC: Gefitinib (Iressa), Erlotinib (Tarceva) | The K-ras gene, a human proto-oncogene, encodes one of the proteins in the EGFR (epidermal growth factor receptor) signaling pathway critical in the development and progression of cancer, particularly CRC and NSCLC. Cancer patients with mutated K-ras are not likely to respond to drugs targeting the EGFR pathway. To avoid unnecessary toxicity and cost, all patients being considered for anti-EGFR therapy should undergo K-ras mutation testing of their tumors. |
| MSI-H or dMMR (mutations in MLH1, MSH2, MSH6, PMS2, or EPCAM) | MSI-H (high rate of variation in microsatellite length exists across the genome) indicates underlying deficiency in DNA mismatch repair (MMR) capability, which in turn is caused by mutations in one of the DNA MMR genes (MLH1, MSH2, MSH6, PMS2, EPCAM). Microsatellite instability-high (MSI-H) status is determined by polymerase chain reaction (PCR) or next-generation sequencing (NGS) based tests, whereas deficient mismatch repair (dMMR) is typically assessed by immunohistochemistry (IHC) | Frequencies of MSI-H/dMMR in advanced/metastatic cancers: 16% endometrial, 9% colorectal, 3% gastric, 5% esophageal, 21% neuroendocrine (gastrointestinal tract), 16% small bowel, 3% squamous (skin), 3% basal cell (skin), 3% bladder, 2% prostate, 1–2% small cell lung, biliary, pancreatic, thyroid or unknown primary | Pembrolizumab (Keytruda) | Pembrolizumab (an immune checkpoint inhibitor) is approved for patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. |
| PD-L1 | PD-L1 protein expression as determined by immunohistochemistry (IHC) | PD-L1 expression level is measured using the tumor proportion score (TPS), the percentage of tumor cells staining for PD-L1 (0–100%). Approximately one-third of NSCLC cases have detectable PD-L1 expression by IHC. | Pembrolizumab (Keytruda) | PD-L1 (programmed death ligand 1) is an immune-related biomarker that can be expressed on tumor cells. PD-L1 testing determines which patients are likely to benefit from treatment with pembrolizumab, which is an immune checkpoint inhibitor that targets PD-L1. Overexpression of PD-L1 is an approved companion diagnostic test for pembrolizumab in NSCLC with no EGFR or ALK aberrations, gastric/gastroesophageal junction cancer, squamous cell esophageal cancer, cervical cancer, and urothelial cancer. |
| Solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene | SLCO1B1*5 (c.521T>C, ↓ for TC-allele and ↓↓ for CC-allele) | 20–30% of the general population are heterozygous (TC-allele, moderate risk) and 2–4% are homozygous (CC-allele, high risk) for the c.521T>C variant. | Simvastatin (Zocor, FloLipid) | SLCO1B1 is an influx transporter that moves drugs into hepatocytes. Decrease in the activity of this transporter (SLCO1B1 c.521T>C variant) is associated with increased blood drug levels and increased risk of statin-induced myopathy and statin intolerance. Genotyping is recommended for patients beginning statin therapy, especially simvastatin therapy. |
| Thiopurine methyltransferase (TPMT) variants | TPMT*2 (238G>C, ↓); TPMT*3A (460G>A and 719A>G, ↓↓); TPMT*3B (460G>A, ↓); TPMT*3C (719A>G, ↓) | About 10–12% of Whites and Blacks have reduced enzyme activity because they are heterozygous for one of the mutant alleles. About 1 in 300 Whites is homozygous for a mutant allele. | Azathioprine (AZA), 6-mercaptopurine (6-MP) | AZA is a prodrug that is metabolized to 6-MP, which is then further metabolized to active 6-thioguanine (6-TG) and inactive 6-methylmercaptopurine (6-MMP) through hypoxanthine phosphoribosyltransferase and TPMT, respectively. Variation in the TPMT gene can result in functional inactivation of the enzyme and an increased risk of life-threatening, 6-TG-associated myelosuppression. TPMT genotyping before instituting AZA or 6-MP can help prevent toxicity by identifying individuals with low or absent TPMT enzyme activity. Patients with homozygous or compound heterozygous mutant alleles (“poor metabolizers”) should not be given AZA or 6-MP, while heterozygotes with a single mutant allele should be treated with lower doses. |
| Uridine diphospho-glucuronosyltransferase 1A1 (UGT 1A1) variants | UGT1A1*28 (7 TA repeats in promoter, ↓) | Homozygosity in 9–23% of Whites, Blacks, and South Asian Indians, and in 1–2% of Eastern Asians. | Irinotecan (Camptosar) | Irinotecan is used in the treatment of metastatic colorectal cancer. It is metabolized to active SN-38, a topoisomerase I inhibitor. SN-38 is further glucuronidated to inactive SN-38G by UGT1A1 and excreted. Heterozygous and homozygous UGT1A1*28 genotypes show a 25% and 70% decrease in enzyme activity, respectively. The presence of the UGT1A1*28 allele is a risk factor for the development of adverse drug reactions (eg, neutropenia, severe diarrhea). Testing for the allele can prevent drug toxicity at high doses of irinotecan. |
| Vitamin K epoxide reductase complex (VKORC1) variants | VKORC1 (–1639G>A) | The homozygous (–1639G>A) allele (–1639AA genotype) is present in approximately 15% of Whites and 80% of Chinese. | Warfarin (Coumadin) | The primary therapeutic target of the anticoagulant warfarin is VKOR. Polymorphisms in the VKOR-encoding gene (VKORC1) explain about 30% of the phenotypic variability in drug effect. Patients carrying certain single nucleotide polymorphisms in the VKORC1 gene (especially the –1639G>A allele) require a lower warfarin maintenance dose to reach a therapeutic INR. |