Table 1.
Select examples of SNPs with clinical significance.
|
Phase I metabolism enzymes, Allele nomenclature for Cytochrome P450 enzymes [24]: | ||||
| Gene | rs# | location | Function | SNPlex |
| CYP2C9 | rs1799853 | *2, R144C | PM 0.25% in Caucasians, life-threatening bleeding after given warfarin | No |
| rs1057910 | *3, I359L | Yes | ||
| CYP2C19 | rs4244285 | *2, 681G>A, exon 5, splicing defect | PM phenotype 2–5% in Caucasians, 18–23% in Asians, > 87% PM in Caucasians is *2 and *3; > 99% PM in Asians has *2 and *3. CYP2C19*2 homozygotes did not respond to antiangiogenic drug thalidomide treatment | No |
| rs4986893 | *3, 17948G>A, exon 4 premature stop | Yes | ||
| rs28399504 | *4, transcription ablation | Failed | ||
| 90033C>T, R433W, *5A, *5B | No enzymatic activity | Yes | ||
| *7, 19294T>A | Splicing defect, no enzymatic activity | Yes | ||
| CYP2D6 | rs16947 | *2, 2851C>T, R296C | Normal, nucleotide position corrected according to [47] | Yes |
| rs3892097 or rs1800716 | *4, 1847G>A, splicing defect | The CYP2D6 PM is about 5–10% of Caucasians. 99% PM has *3, *4, *5, *6, *7, *8 and *11. *3, *5 and *6 are deletions | Yes | |
| rs28371704 | 983A>G, H94R | In *4A, *4B, *4F, *4G, *4H and *4J | Failed | |
| rs5030867 | *7, 2936A>C, H324P | No enzymatic activity | Yes | |
| rs5030865 | *8, 1759G>T | Stop codon, no enzymatic activity | Yes | |
| rs1065852 | *10, 100C>T, P34S | Decrease enzymatic activity | Yes | |
| rs5030863 | *11, 882G>C | Splicing defect, no enzymatic activity | Yes | |
| rs28371706 | *17, 1022C>T, T107I | Decrease enzymatic activity | Yes | |
| rs28371717 | *33, 2484G>T, A237S | Normal | Yes | |
| *44, 2951G>C | Splicing defect, no enzymatic activity | Yes | ||
| CYP3A4 | rs11773597 | *1F, m747C>G | Trans-regulation of gene expression is important. Overall, no major pharmacokinetic consequences for the identified CYP3A4 SNPs have been observed for the metabolism of anti-cancer drugs [12] | Yes |
| rs2740574 | *1B, m392A>G | Yes | ||
| Yes | ||||
| *4, 13989A>G, | In AF209389 | Yes | ||
| *8, 14026G>A | In AF209389, R130Q | Yes | ||
| CYP3A5 | rs28365083 | *2, 27289C>A, T398N | Failed | |
| rs776746 | *3, 6986A>G, splicing inclusion | *3 is the most frequent polymorphism (about 90% in Caucasians). Splicing defect, severely decrease of enzymatic activity [12] | Yes | |
| rs28365085 | *3d, 31551T>C, I488T | Yes | ||
| *5, 12952T>C | Splicing defect | Yes | ||
| *8, 3699C>T, R28C | Decreased enzymatic activity | Yes | ||
| rs28383479 | *9, 19386G>A, A337T | Decreased enzymatic activity | Failed | |
| rs15524 | *10, 31611C>T | Decreasde enzymatic activity | Yes | |
| DPYD | rs3918290 | splice variant IVS14+1G>A | *2A, Skipping exon 14, ↑ 5FU neurotoxicity [12] | Yes |
| NQO1 | rs1800566 | *2, C609T, R187S | *2 and *3 have reduced protein level and enzymatic activity. NQO1 is needed for the activation of mitomycin C, 17AAG (HSP90 inhibitor) and inactivation of benzene-like leukemogenic agents [13] | Yes |
| rs4986998 | *3, C465T, R139W | Yes | ||
|
Phase II metabolism enzymes NAT allele nomenclature [26]: UGT allele nomenclature [25]: | ||||
| Gene | rs# | location | Function | SNPlex |
| NAT2 | rs1801280 | 341T>C, I114T, *5A to*5J, *14C and *14F | Alleles with decreased activity include NAT2*5B, NAT2*6A, NAT*7A or B, NAT2*10, NAT2*14A or B, NAT2*17, NAT2*18 and NAT2*19 [12, 14] Low NAT2 activity is related to the increased risk of isoniazid hepatotoxicity |
Yes |
| rs1799929 | 481C>T, L161L, *5A, *5B, *5F, *5G, *5H, *5I, *6E, *11A, *11B, *12C and *14C | Yes | ||
| rs1208 | 803A>G, K268R,*5B, *5C, *5F, *5G, *5H, *5I, *6C, *12A, *12B, *12C, *12D, *14E and *14F | Yes | ||
| rs1041983 | 282C>T, Y94Y, *13, *5G, *5J, *6A, *6C, *6D, *7B, *12B, *14B, *14D, *14G | Yes | ||
| rs1799930 | 590G>A, R197Q *5E, *5J, *6A, *6B to *6E, *14D | Yes | ||
| rs1799931 | , 857G>A, G286E *7A, *7B | Yes | ||
| 499G>A in sequence X14672, E167K, *10 | Yes | |||
| rs1801279 | 191G>A, R64Q *14A to *14G, | Yes | ||
| 434A>C A in sequence X14672, Q145P, *17 | Yes | |||
| 845A>C A in sequence X14672, K282T, *18 | Yes | |||
| rs1805158 | 190C>T, R64W, *19 | Yes | ||
| TPMT | rs1800462 | *2, 238G>C | Null genotype associated with hematopoietic thiopurine toxicity, homozygous frequency 1/300 [4] | No |
| rs1800460 | *3A, 460G>A | No | ||
| rs1142345 | *3C, 719A>G | No | ||
| UGT1A1 | TA (5–8) TAA | UGT1A1 *28 (7 TAs) associated with increased irinotecan toxicity. Caucasians ~32% | No | |
| rs4148323 | 211G>A, G71R, *6 | Reduced enzymatic activity | Yes | |
| rs34993780 | 1456T>G, Y486D, *7 | Yes | ||
| rs35350960 | 686C>A, P229Q, *27 | Yes | ||
| 247T>C, F83L, *62 | Causing Gilbert's syndrome | Yes | ||
| GSTT1 | Deletion causing null genotype | Null allele has been associated with better or poorer survival in leukemia patients following chemotherapy [12] | No | |
| GSTP1 | rs947894 | 313A>G I105V | Val associated with decreased enzyme activity and increased survival after 5FU/oxaliplatin treatment of colorectal cancer patients [54] | Yes |
| GSTM1 | Deletion causing null genotype | Null allele is associated with increased survival after chemotherapy for multiple cancers [13, 14] | No | |
| SULT1A1 | rs9282861 | *2, R213H, HaeII | His/His has lower enzymatic activity and is associated with poor survival following tamoxifen therapy [55] | No |
| Transporter Genes | ||||
| Gene | rs# | location | Function | SNPlex |
| ABCB1 | rs1045642 | 3435C>T | C3435 associated with higher drug transport activity | Yes |
| rs1128503 | 1236T>C | Yes | ||
| rs2229109 | 1199G>A | Yes | ||
| ABCC2 | rs2273697 | 1249G>A, Val417Ile | 1249AA associated with decreased mRNA [56] | Yes |
| ABCG2 | rs2231142 | 421C>A, Q141K | Minor alleles with lower BRCP expression, enhanced drug sensitivity [12] | Yes |
| rs2231137 | G34 G>A V12M | No | ||
| 944–949 deletion | No | |||
| SLC19A1 | rs1051266 | 80G>A Arg27His | Patients with the 80AA genotype had higher plasma MTX levels, suggesting decreased cellular uptake of MTX | Yes |
| SLCO1B1/SCL21A6 | rs4149056 | T521C, Val174Ala, *5 | *5 and *15 are associated with decreased transport activity [57] | Yes |
| rs2306283 | Asp130Asn, *15 | Yes | ||
| DNA repair genes | ||||
| Gene | rs# | location | Function | SNPlex |
| BRCA2 | rs144848 | N372H | Cancer risk [51] | Yes |
| OGG1 | rs1052133 | S326C | Cancer risk [51] | Yes |
| XRCC1 | rs1799782 | R194W | Cancer risk [51] | Yes |
| rs25487 | R399Q | Gln399 associated with oxaliplatin/5-FU resistance | Yes | |
| rs25489 | R280H | Yes | ||
| ERCC2/XPD | rs13181 | K751Q | Lys751 associated with improved oxaliplatin/5-FU treatment outcome [52] | Yes |
| TP53 | rs1042522 | R72P | Cancer risk | Failed |
| MGMT | rs12917 | 262C>T, L84F | Decreased repair of DNA damage [58] | Yes |
| CHEK2 | 1100delC | Protein truncation, cancer risk [59] | No | |
| Drug target, pathway genes | ||||
| Gene | rs# | location | Function | SNPlex |
| DHFR | rs5030762 | 829T>C | SNP 829T>C located in the untranslated region of the DHFR, associated with ↑ of DHFR mRNA, ↓ responsiveness to methotrexate | No |
| MTHFR | rs1801133 | 677C>T, A222V | minor allele frequency 24–46%% in Caucasians, T allele is associated with reduced enzyme activity, increased toxicity to methotrexate [13, 53] | Yes |
| rs1801131 | 1298A>C, E429A | Reduced MTHFR enzyme activity [13, 53] | Yes | |
| TYMS | 2–9 28 bp repeats in the 5' promoter enhancer | 3 repeats ↑ RNA, TSER*3 associated with drug resistance of 5FU and methotrexate | No | |
| CDA | rs2072671 | 79A>C, K27Q | Minor allele has lower activity to inactivate gemcitabine than the wild-type [60] | Yes |
| 208G>A, A70T | 70TT has lower activity to inactive cytidine and ara-C than the wild-type [61] | Yes | ||
| Cell cycle genes | ||||
| CCND1 | rs603965 | 870A>G | Alternative transcript encodes a protein with enhanced cell transformation activity, and modifies caner risk [62] | Yes |