Table 5. Worldwide distribution pattern of KRAS, NRAS, BRAF, PIK3CA, APC, and TP53 mutations.
| Region | Year | Method and codons studied | Number of patients tested | Number of patients with mutations in the indicated gene (%) | References | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| KRAS | NRAS | BRAF | PIK3CA | APC | TP53 | |||||
| Middle Eastern countries | 2,981 | 691/2,052 (33.70) | 4/99 (4.0) | 76/1,647 (4.60) | 51/418 (12.00) | 59/177 (33.0) | 208/541 (38.40) | |||
| Arabian Peninsula | 2015 | Next-generation sequencing | 99 | 44 (44.00) | 4 (4.0) | 4 (4.00) | 13 (13.00) | 27 (27.3) | 52 (52.00) | Current study |
| Egypt | 2001 | PCR and SequiTherm EXCEL IITM DNA sequencing; codons: 12, 13, immunohistochemistry for TP53, exons: 5–9 | 59 | 5/47 (11.00) | Not done | Not done | Not done | Not done | 26/56 (46.00) | (22) |
| Saudi Arabia | 2008 | PCR amplification and direct sequencing, exons: 9, 20, exons: 5–8 | 448 | Not done | Not done | Not done | 51/418 (12.00) | Not done | 130/386 (33.70) | (27) |
| Tunisia | 2008 | PCR, codons: 1240–1513 | 48 | Not done | Not done | 4/48 (8.00) | Not done | 25/48 (52.0) | Not done | (28) |
| Iran | 2011 | PCR-RFLP, codon: 600 | 110 | 24/86 (28.00) | Not done | 0 | Not done | Not done | Not done | (29) |
| Jordan | 2012 | Hybridization-based strip assay, RT-PCR-based assay, Sanger sequencing, codons: 12, 13 | 100 | 44 (44.00) | Not done | Not done | Not done | Not done | Not done | (20) |
| Iraq | 2012 | PCR and reverse hybridization | 50 | 24 (48.00) | Not done | Not done | Not done | Not done | Not done | (30) |
| Turkey | 2013 | AutoGenomics INFINITI® assay, codons: 12, 13, 61 | 53 | 26 (49.05) | Not done | 0 | Not done | Not done | Not done | (31) |
| Saudi Arabia | 2014 | LCD-array kit | 83 | 35/83 (42.20) | Not done | Not done | Not done | Not done | Not done | (32) |
| Saudi Arabia | 2014 | Direct DNA sequencing, codons: 12, 13, codon: 600 | 770 | 216/755 (28.60) | Not done | 19/757 (2.50) | Not done | Not done | Not done | (19) |
| Saudi Arabia | 2014 | PCR, codons: 12, 13 | 150 | 84/150 (56.00) | Not done | Not done | Not done | Not done | Not done | (33) |
| Iran | 2014 | PCR-RFLP, codon: 600 | 80 | Not done | Not done | 37/80 (46.25) | Not done | Not done | Not done | (34) |
| Iran | 2014 | Direct DNA sequencing, codons: 653–885, 853–1242, 1213–1482, and 1404–1613 of exon 15 | 30 | Not done | Not done | Not done | Not done | 7 (23.3) | Not done | (35) |
| Saudi Arabia | 2015 | PCR, codons: 12, 13, codon: 600 | 770 | 150/498 (30.10) | Not done | 12/500 (2.40) | Not done | Not done | Not done | (24) |
| Turkey | 2015 | Pyrosequencing with PCR, codons: 12, 13, 61 | 31 | 7/31 (22.00) | Not done | Not done | Not done | Not done | Not done | (36) |
| Iran | 2015 | PCR and direct sequencing by Sanger method | 100 | 32 (32.00) | Not done | Not done | Not done | Not done | Not done | (37) |
| Western countries | 22,441 | 7,497/21,212 (35.30) | 183/4,781 (3.8) | 1,011/11,100 (9.10) | 1,336/9,696 (13.80) | 626/1,540 (40.6) | 169/308 (54.90) | |||
| Norway | 2002 | PCR, codons: 653–2843 | 218 | Not done | Not done | Not done | Not done | 144 (66.0) | Not done | (38) |
| United Kingdom | 2002 | Direct sequencing, codons: 12, 13, 61, denaturing HPLC “WAVE” analysis, codons: 1028–1712 | 106 | 29/106 (27.40) | Not done | Not done | Not done | 60/106 (56.0) | 65/106 (61.30) | (39) |
| Portugal | 2005 | PCR-SSCP automated sequencing, exon: 9; PCR automated sequencing, exon: 20 | 150 | 31 (20.70) | Not done | 18 (12.00) | 14 (9.30) | Not done | Not done | (40) |
| Netherlands | 2005 | Nested PCR, followed by direct sequencing, exon: 1, codons: 1286–1520 | 656 | 235/656 (35.80) | Not done | Not done | Not done | 245 (37.3) | Not done | (41) |
| USA | 2007 | PCR, codons: 1286–1585 | 90 | 29 (32.20) | Not done | 18 (20.00) | Not done | 31 (34.4) | 41 (45.60) | (42) |
| Germany | 2007 | PCR, codons: 1260–1547, exons: 5–8 (TP53) | 99 | Not done | Not done | Not done | Not done | 49 (49.0) | 52 (52.00) | (43) |
| France | 2008 | PCR then direct sequencing, exon: 2, exons: 1, 2, 9, 20 (PIK3CA) | 586 | 198 (33.80) | Not done | 78 (13.30) | 98 (16.70) | Not done | Not done | (44) |
| Hungary | 2008 | PCR and SSCP/heteroduplex analysis, codons: 1285–1465 | 70 | Not done | Not done | Not done | Not done | 15 (21.4) | Not done | (45) |
| USA | 2008 | PCR, exon: 2, exons: 11, 15, DNA sequencing using a BigDye® 3.1 Terminator kit | 62 | 24 (38.70) | Not done | 4 (5.60) | 2 (3.20) | Not done | Not done | (46) |
| Italy | 2008 | HRM analysis, exon: 2, exon: 15, exons: 9, 20 | 116 | 50 (43.00) | Not done | 11 (9.50) | 20 (17.20) | Not done | Not done | (47) |
| Italy | 2009 | PCR, codons: 12, 13, exons: 11, 15, exons: 9, 20 | 32 | 7/29 (24.10) | Not done | 3/31 (9.67) | 4/31 (12.90) | Not done | Not done | (48) |
| USA | 2009 | PCR and pyrosequencing, codons: 12, 13, codon: 600, exons: 9, 20 | 450 | 160/448 (35.70) | Not done | 69/438 (15.80) | 82 (18.20) | Not done | Not done | (49) |
| United Kingdom | 2009 | PCR, then Sequenom mass-spectrometric genotyping, (first sample), PCR, then Sanger sequencing (second sample), exon: 2, exon: 15, exons: 9, 20 | 168 | 62 (36.90) | Not done | 13 (7.70) | 26 (15.47) | Not done | Not done | (50) |
| Belgium | 2010 | Mass spectrometry genotyping | 1,022 | 299/747 (40.00) | 17/644 (2.6) | 36/761 (4.70) | 108/743 (14.50) | Not done | Not done | (13) |
| Germany | 2010 | Two multiplex PCRs: the first for BRAF exon 15 and KRAS exons 2 and 3 and the second for PIK3CA exons 9 and 20 and NRAS exons 2 and 3 | 294 | 119/245 (48.60) | 6/294 (2.0) | 13/245 (5.30) | 32/245 (13.10) | Not done | Not done | (51) |
| France | 2010 | KRAS: allelic discrimination assay; checked by direct sequencing of exon 2, BRAF(V600E): allelic discrimination assay; checked by direct sequencing; PIK3CA: direct sequencing, then DNA analyzer automated sequencer | 42 | 19 (45.20) | Not done | 1 (2.38) | 6 (14.28) | Not done | Not done | (52) |
| USA | 2011 | Pyrosequencing, codons: 12, 13, 61, codons: 595–600; PCR, then Sanger sequencing (PIK3CA), codons: 532–554 of exon 9, 1011–1062 of exon 20 | 504 | 69/367 (18.80) | 2/31 (6.0) | 31/361 (8.60) | 54 (11.00) | Not done | Not done | (53) |
| Italy | 2012 | HRM analysis and direct sequencing, exon: 2, exon: 15, exon: 20 | 209 | 90 (43.00) | Not done | 13/117 (11.10) | 7 (3.30) | Not done | Not done | (54) |
| Sardinia | 2012 | Automated DNA sequencing, exons: 2, 3, exon: 15, exons: 9, 20 | 478 | 145/478 (30.30) | Not done | 1/384 (0.26) | 67/384 (17.44) | Not done | Not done | (55) |
| USA | 2013 | Pyrosequencing, codons: 12, 13, codon: 600, exons: 9, 20 | 964 | 336/959 (35.00) | Not done | 131/959 (13.70) | 161/964 (16.70) | Not done | Not done | (56) |
| Portugal | 2013 | HRM, then DNA sequencing, exons: 3, 4 (KRAS), exons: 11, 15, exons: 9, 20 (PIK3CA) | 201 | 26 (12.90) | Not done | 11 (5.50) | 22 (10.90) | Not done | Not done | (57) |
| Russia | 2013 | HRM and sequencing COLD-PCR/sequencing, allele-specific PCR | 195 | 70 (35.90) | 8 (4.1) | 8 (4.10) | 24 (12.30) | Not done | Not done | (58) |
| Australia | 2013 | Direct sequencing, exons: 9, 20 | 757 | 215 (28.40) | Not done | 120 (15.90) | 105 (14.00) | Not done | Not done | (59) |
| France | 2013 | PCR amplification followed by direct sequencing, exons: 2, 3, exon: 15, exons: 9, 20 | 98 | 23 (23.50) | Not done | 2 (2.00) | 4 (4.00) | Not done | Not done | (60) |
| Germany | 2013 | Pyrosequencing, exon: 2, exon: 15, exons: 9, 20 | 171 | 70 (40.90) | Not done | 19 (11.10) | 20 (18.70) | Not done | Not done | (61) |
| Albania | 2014 | Direct sequencing, codons: 12, 13, 61, 146, codon: 600 | 159 | 28 (17.60) | Not done | 10 (6.30) | Not done | Not done | Not done | (62) |
| United Kingdom | 2013 | Pyrosequencing (KRAS), codons: 12, 13, Sequenom, Sanger sequencing, codons: 12, 13, codon: 600 | 1,976 | 836 (42.30) | 71 (3.6) | 178 (9.00) | 251 (12.70) | Not done | Not done | (18) |
| Greece | 2014 | PCR, mutation analysis methodology of increased sensitivity and conventional genomic dideoxy sequencing (PIK3CA) | 171 | 92 (53.80) | Not done | 4/171 (2.30) | 6/171 (3.50) | Not done | Not done | (63) |
| Brazil | 2014 | Direct sequencing, codons: 12, 13 | 8,234 | 2,627 (31.90) | Not done | Not done | Not done | Not done | Not done | (64) |
| Chile | 2014 | PCR, codons: 12, 13 | 262 | 98 (37.00) | Not done | Not done | Not done | Not done | Not done | (65) |
| Italy | 2015 | Pyrosequencing, codons: 12, 13, 61, 146, codon: 600, exons: 9, 20 | 194 | 92 (47.40) | 7/194 (3.6) | 10 (19.40) | 32 (16.50) | Not done | Not done | (66) |
| USA | 2014 | Not reported | 484 | 240 (49.60) | 32 (7.4) | 10 (4.10) | Not done | Not done | Not done | (67) |
| Greece | 2015 | PCR, codons: 12, 14, 61, 146, codon: 600, bidirectional sequence analysis | 322 | 118 (36.60) | Not done | 17/188 (9.00) | Not done | Not done | Not done | (68) |
| Italy | 2015 | Mass spectrometry-based single-base extension technique, codons (KRAS): 12, 13, 59, 61, 117, 146, codons (NRAS): 12, 13, 18, 59, 61, 117, 146, codons (BRAF): 594, 600, 601 | 175 | 25 (14.00) | 4 (3.0) | 13 (7.00) | Not done | Not done | Not done | (69) |
| Brazil | 2015 | Pyrosequencing method improved by nested PCR, codons: 12, 13 | 422 | 139/421 (33.00) | Not done | Not done | Not done | Not done | Not done | (70) |
| Belgium | 2015 | RT-PCR and Sequenom, exons: 2–4 | 193 | 53/165 (32.10) | 4 (2.4) | 26/165 (15.80) | 22/165 (13.30) | Not done | Not done | (71) |
| USA | 2015 | PCR, codons: 12, 13 | 331 | 91 (27.50) | Not done | Not done | Not done | Not done | Not done | (72) |
| Italy | 2015 | Pyrosequencing, exon: 2, codon: 600 | 309 | 143/307 (46.60) | 17/307 (5.5) | 12 (4.00) | Not done | Not done | Not done | (73) |
| France | 2015 | Next-generation sequencing | 13 | 7 (53.80) | Not done | Not done | Not done | 13/13 (100.0) | 11/13 (84.60) | (74) |
| Germany | 2015 | PCR, codons: 12, 13, codon: 600 | 99 | 33 (33.30) | Not done | 9 (9.00) | Not done | Not done | Not done | (75) |
| France | 2015 | PCR, codons: 12, 13, codon: 600 | 180 | 93 (51.70) | Not done | 19 (10.60) | Not done | Not done | Not done | (76) |
| France | 2015 | Direct Sanger sequencing and PCR, codons: 12, 13, codon: 600, exons: 9, 20 | 826 | 301/817 (37.00) | Not done | 85/780 (11.00) | 113 (14.00) | Not done | Not done | (77) |
| USA | 2015 | Next-generation sequencing | 353 | 175/288 (49.60) | 15/288 (4.3) | 18/288 (5.10) | 56/288 (13.90) | 69/288 (24.0) | Not done | (78) |
| Asian countries | 8,053 | 2,797/7,973 (35.10) | 108/3,041 (3.6) | 292/5,922 (4.90) | 362/4,238 (8.50) | 85/262 (32.4) | 244/608 (40.10) | |||
| Japan | 2002 | PCR-SSCP method, codons: 12, 14, codons: 582–1580, codons: 33–367 | 61 | 22/61 (36.00) | Not done | Not done | Not done | 29/61 (47.5) | 35/61 (57.40) | (79) |
| South Korea | 2008 | WAVE DHPLC system, codon: 12, codons: 1202–1674, exons: 4–9 | 78 | 23 (29.50) | Not done | Not done | Not done | 26 (33.3) | 27 (34.60) | (80) |
| China | 2010 | Multiplex PCR for TP53 and PTEN amplification; singleplex PCR using HotStarTaq (QIAGEN) to amplify PIK3CA, KRAS, and BRAF amplicons, codons: 12, 13, 61 (KRAS), codon: 600 (BRAF) | 181 | 58 (32.00) | Not done | 29 (16.00) | 7 (3.00) | Not done | 92 (52.00) | (81) |
| China | 2010 | Pyrosequencing using a PyroMark ID system (Biotage AB, Sweden), codons: 12, 13, codon: 600 | 61 | 12 (19.70) | Not done | 3 (4.90) | 3 (4.90) | Not done | Not done | (82) |
| Korea | 2011 | Direct sequencing and peptide nucleic acid-mediated PCR | 92 | 19 (20.70) | Not done | 3 (3.30) | 1 (1.10) | Not done | Not done | (83) |
| Japan | 2011 | Direct sequencing | 134 | 41 (30.60) | Not done | 1 (0.75) | 18 (13.40) | Not done | Not done | (84) |
| Taiwan (China) | 2012 | Direct sequencing; HRM analysis, codon: 600, exons: 9, 20 (PIK3CA) | 182 | 61 (33.50) | Not done | 2 (1.10) | 13 (7.10) | Not done | Not done | (85) |
| China | 2012 | PCR-based direct DNA sequencing, codons: 12, 13 | 331 | 137/311 (44.10) | Not done | 9/156 (5.80) | 4/156 (2.60) | Not done | Not done | (86) |
| China | 2012 | Automated sequencing analysis, codons: 12–14, codon: 600, codons: 542, 545, 1047 | 69 | 25/57 (53.90) | Not done | 15/59 (25.40) | 5/56 (8.90) | Not done | Not done | (87) |
| Japan | 2013 | Multiplex kit (Luminex xMAP tests) and direct sequencing methods, codons: 61, 146, codon: 600, codons: 542, 545, 546, 1047 | 82 | 21 (25.60) | 2 (2.4) | 4 (4.90) | 4 (4.90) | Not done | Not done | (88) |
| Malaysia | 2013 | Direct DNA sequencing, quantitative real-time PCR, codons: 12, 13, 61, codon: 600 | 44 | 11 (25.00) | Not done | 1 (2.30) | 33/43 (76.70) | Not done | Not done | (89) |
| Japan | 2013 | Direct sequencing | 254 | 85 (33.50) | Not done | 17 (6.70) | Not done | Not done | Not done | (90) |
| Japan | 2013 | Automated CEQ 2000XL DNA analysis system | 43 | 12 (27.90) | Not done | 2 (4.70) | 2 (4.70) | Not done | Not done | (91) |
| Taiwan (China) | 2013 | Primer extension analysis, codons: 12, 13, HRM analysis, codon: 600, direct sequencing (for TP53), exons: 5–8 | 165 | 61/165 (36.97) | Not done | 7/165 (4.24) | Not done | Not done | 62/165 (37.58) | (92) |
| India | 2013 | PCR, exon: 2 (KRAS) | 1,323 | 271 (20.50) | Not done | Not done | Not done | Not done | Not done | (93) |
| India | 2013 | PCR-RFLP and direct sequencing | 62 | 41 (66.10) | Not done | Not done | Not done | Not done | Not done | (94) |
| India | 2013 | PCR-restriction digestion to detect KRAS mutations, PCR-SSCP followed by DNA sequencing to detect mutations in APC and TP53 genes | 30 | 8 (26.70) | Not done | Not done | Not done | 14 (46.7) | 6 (20.00) | (95) |
| India | 2014 | Nested PCR, codons: 12, 13; PCR and direct sequencing, codon: 600; hemi-nested and nested PCR, exons: 9, 20 | 204 | 48 (23.50) | Not done | 20 (9.80) | 12 (5.90) | Not done | Not done | (96) |
| Pakistan | 2014 | PCR, codons: full coding region of KRAS | 150 | 20/150 (13.00) | Not done | Not done | Not done | Not done | Not done | (97) |
| China | 2014 | Torrent AmpliSeq Cancer Panel | 93 | 47 (50.50) | 3 (3.2) | 1 (1.10) | 10 (10.80) | 16 (17.2) | 22 (23.70) | (98) |
| Japan | 2015 | Denaturing gradient gel electrophoresis; PCR (for BRAF) | 813 | 312/812 (38.00) | Not done | 40/811 (5.00) | Not done | Not done | Not done | (99) |
| China | 2015 | Sanger sequencing; mutation system PCR (nine patients), codons: 12, 13, codon: 600 | 535 | 185/488 (37.90) | Not done | 20/450 (4.40) | Not done | Not done | Not done | (100) |
| Japan | 2015 | Luminex xMAP technology, codons: 61, 146, codon: 600, codons: 542, 545, 546, 1047; Scorpion assay, codons: 12, 13 | 264 | 100/264 (37.90) | 11/264 (4.2) | 14/264 (5.40) | 17/264 (6.40) | Not done | Not done | (101) |
| Singapore | 2015 | Direct sequencing | 45 | 15 (33.30) | Not done | 0 | 1 (2.20) | Not done | Not done | (102) |
| China | 2015 | RT-PCR and Sanger sequencing, codons: 12, 13, 61, 117, 146, codon: 600, codon: 1047 | 1,110 | 504/1,110 (45.40) | 43/1,110 (3.9) | 34/1,110 (3.10) | 39/1,110 (3.50) | Not done | Not done | (9) |
| South Korea | 2015 | Not reported | 100 | 26 (26.00) | Not done | Not done | Not done | Not done | Not done | (103) |
| Japan | 2015 | PCR and direct sequencing, exon: 2 | 55 | 30 (54.40) | Not done | Not done | Not done | Not done | Not done | (104) |
| Taiwan (China) | 2015 | PCR and Sequenom | 1,492 | 602 (40.30) | 49 (3.3) | 70 (4.70) | 193 (12.90) | Not done | Not done | (105) |
| Pooled results for all studies from all regions | 33,475 | 10,985/31,237 (35.20) | 33,475 | 1,379/18,669 (7.40) | 1,749/14,352 (12.20) | 770/1,980 (38.9) | 621/1,457 (42.60) | |||
PCR, polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; RFLP, restriction fragment length polymorphism; HPLC, high-performance liquid chromatography; SSCP, single-strand conformation polymorphism; HRM, high-resolution melting; COLD, co-amplification at lower denaturation temperature; DHPLC, denaturing high-performance liquid chromatography.