Introduction
Results
KRAS codon 12, 13, 61 and 146 mutations, in relation to clinicopathological and molecular features
Codon | Nucleotide change | Amino acid change | Codon change | No. of cases | Proportion among 1267 cases |
---|---|---|---|---|---|
Any | Any | Any | Any | 505 | 40% |
12 | Any | Any | Any | 344 | 27% |
13 | Any | Any | Any | 115 | 9.1% |
61 | Any | Any | Any | 19 | 1.5% |
146 | Any | Any | Any | 40 | 3.2% |
Mutations identified in only one of codons 12, 13, 61 and 146 | |||||
12 | c.34G>A | p.G12S | GGT>AGT | 12 | 1.0% |
12 | c.34G>C | p.G12R | GGT>CGT | 7 | 0.6% |
12 | c.34G>T | p.G12C | GGT>TGT | 43 | 3.4% |
12 | c.35G>A | p.G12D | GGT>GAT | 157 | 12% |
12 | c.35G>C | p.G12A | GGT>GCT | 20 | 1.6% |
12 | c.35G>T | p.G12V | GGT>GTT | 93 | 7.3% |
12 | c.35_36delinsCA | p.G12A | GGT>GCA | 1 | 0.1% |
13 | c.37G>C | p.G13R | GGC>CGC | 1 | 0.1% |
13 | c.37G>T | p.G13C | GGC>TGC | 2 | 0.2% |
13 | c.38G>A | p.G13D | GGC>GAC | 103 | 8.1% |
13 | c.38G>T | p.G13V | GGC>GTC | 2 | 0.2% |
61 | c.182A>G | p.Q61R | CAA>CGA | 2 | 0.2% |
61 | c.182A>T | p.Q61L | CAA>CTA | 4 | 0.3% |
61 | c.183A>C | p.Q61H | CAA>CAC | 7 | 0.6% |
60, 61 | c.180_181delinsAA | p.Q61K | GGT + CAA>GGA + AAA | 4 | 0.3% |
146 | c.436G>A | p.A146T | GCA>ACA | 21 | 1.7% |
146 | c.436G>C | p.A146P | GCA>CCA | 3 | 0.2% |
146 | c.437C>T | p.A146V | GCA>GTA | 11 | 0.9% |
Mutations identified in two or more of codons 12, 13, 61 and 146 | |||||
12, 13 | c.35G>A, c.38G>A | p.G12D, p.G13D | GGT>GAT, GGC>GAC | 4 | 0.3% |
12, 13 | c.35G>T, c.37G>T | p.G12V, p.G13C | GGT>GTT, GGC>TGC | 1 | 0.1% |
12, | c.35G>T, | p.G12V, | GGT>GTT, GGT + CAA>GGA + AAA | 1 | 0.1% |
60, 61 | c.180_181delinsAA | p.Q61K | |||
12, 146 | c.34G>C, c.436G>A | p.G12R, p.A146T | GGT>CGT, GCA>ACA | 1 | 0.1% |
12, 146 | c.34G>T, c.436G>A | p.G12C, p.A146T | GGT>TGT, GCA>ACA | 1 | 0.1% |
12, 146 | c.34G>T, c.437C>T | p.G12C, p.A146V | GGT>TGT, GCA>GTA | 1 | 0.1% |
12, 146 | c.35G>T, c.436G>A | p.G12V, p.A146T | GGT>GTT, GCA>ACA | 1 | 0.1% |
13, 146 | c.38G>A, c.436G>A | p.G13D, p.A146T | GGC>GAC, GCA>ACA | 1 | 0.1% |
12, 13, 61 | c.35G>A, c.38G>A, c.183A>T | p.G12D, p.G13D, p.Q61H | GGT>GAT, GGC>GAC, CAA>CAT | 1 | 0.1% |
Clinicopathological or molecular feature | Total No. |
KRAS
| P(Wild-type vs. mutant) | KRAS mutations identified in only one codon | P(Across four mutants) | ||||
---|---|---|---|---|---|---|---|---|---|
Wild-type | Mutant | Codon 12 | Codon 13 | Codon 61 | Codon 146 | ||||
Total No. of patients | 1267 | 762 | 505 | 333 | 108 | 17 | 35 | ||
Sex | 0.0091 | 0.11 | |||||||
Male | 573 (45%) | 322 (42%) | 251 (50%) | 162 (49%) | 59 (55%) | 4 (24%) | 19 (54%) | ||
Female | 694 (55%) | 440 (58%) | 254 (50%) | 171 (51%) | 49 (45%) | 13 (76%) | 16 (46%) | ||
Mean age (years) ± SD | 68.6 ± 8.7 | 68.4 ± 8.6 | 68.8 ± 8.8 | 0.47 | 69.5 ± 8.5 | 67.5 ± 9.2 | 70.0 ± 9.3 | 66.0 ± 9.8 | 0.065 |
BMI (kg/m2) | 0.13 | 0.43 | |||||||
<30 | 1025 (81%) | 607 (80%) | 418 (83%) | 278 (84%) | 88 (81%) | 11 (69%) | 30 (86%) | ||
≥30 | 240 (19%) | 155 (20%) | 85 (17%) | 54 (16%) | 20 (19%) | 5 (31%) | 5 (14%) | ||
Year of diagnosis | 0.26 | 0.032 | |||||||
Prior to 1998 | 640 (51%) | 375 (49%) | 265 (52%) | 164 (49%) | 63 (58%) | 5 (29%) | 23 (66%) | ||
1998 - 2006 | 627 (49%) | 387 (51%) | 240 (48%) | 169 (51%) | 45 (42%) | 12 (71%) | 12 (34%) | ||
Family history of colorectal cancer in first degree relative(s) | 0.76 | 0.87 | |||||||
Absent | 1026 (81%) | 612 (80%) | 414 (82%) | 273 (82%) | 89 (82%) | 14 (82%) | 27 (77%) | ||
Present in one first degree relative | 179 (14%) | 111 (15%) | 68 (13%) | 44 (13%) | 15 (14%) | 3 (18%) | 5 (14%) | ||
Present in two or more first degree relatives | 62 (5%) | 39 (5%) | 23 (5%) | 16 (5%) | 4 (4%) | 0 | 3 (9%) | ||
Tumor location | <0.0001 | 0.50 | |||||||
Cecum | 209 (17%) | 90 (12%) | 119 (24%) | 79 (24%) | 27 (25%) | 4 (24%) | 6 (18%) | ||
Ascending colon | 262 (21%) | 171 (23%) | 91 (18%) | 52 (16%) | 25 (24%) | 3 (18%) | 7 (21%) | ||
Hepatic flexure to transverse colon | 117 (9%) | 78 (10%) | 39 (8%) | 26 (8%) | 7 (6%) | 4 (24%) | 2 (5%) | ||
Splenic flexure to descending colon | 90 (7%) | 57 (8%) | 33 (6%) | 22 (7%) | 7 (6%) | 0 | 3 (8%) | ||
Sigmoid colon | 297 (24%) | 182 (24%) | 115 (23%) | 83 (25%) | 22 (20%) | 1 (5%) | 8 (24%) | ||
Rectum | 279 (22%) | 176 (23%) | 103 (21%) | 67 (20%) | 20 (19%) | 5 (29%) | 8 (24%) | ||
Disease stage | 0.028 | 0.89 | |||||||
I | 298 (23%) | 190 (25%) | 108 (21%) | 77 (23%) | 20 (19%) | 4 (23%) | 4 (11%) | ||
II | 354 (28%) | 230 (30%) | 124 (25%) | 77 (23%) | 30 (28%) | 5 (29%) | 11 (32%) | ||
III | 328 (26%) | 183 (24%) | 145 (29%) | 97 (29%) | 29 (27%) | 3 (18%) | 11 (32%) | ||
IV | 173 (14%) | 93 (12%) | 80 (16%) | 51 (15%) | 18 (16%) | 2 (12%) | 6 (17%) | ||
Unknown | 114 (9%) | 66 (9%) | 48 (9%) | 31 (10%) | 11 (10%) | 3 (18%) | 3 (8%) | ||
Tumor differentiation | <0.0001 | 0.55 | |||||||
Well-moderate | 1137 (90%) | 663 (88%) | 474 (94%) | 314 (95%) | 99 (92%) | 16 (94%) | 34 (97%) | ||
Poor | 123 (10%) | 94 (12%) | 29 (6%) | 17 (5%) | 9 (8%) | 1 (6%) | 1 (3%) | ||
Peritumoral lymphocytic reaction | 0.042 | 0.48 | |||||||
Absent-minimal | 164 (14%) | 96 (13%) | 68 (14%) | 47 (15%) | 14 (13%) | 2 (12%) | 4 (12%) | ||
Mild | 878 (72%) | 515 (71%) | 363 (75%) | 237 (75%) | 76 (71%) | 12 (76%) | 28 (85%) | ||
Moderate-marked | 170 (14%) | 117 (16%) | 53 (11%) | 32 (10%) | 17 (16%) | 2 (12%) | 1 (3%) | ||
MSI status | <0.0001 | 0.078 | |||||||
MSI-low/MSS | 1057 (85%) | 587 (79%) | 470 (94%) | 315 (95%) | 100 (94%) | 14 (82%) | 31 (89%) | ||
MSI-high | 191 (15%) | 160 (21%) | 31 (6.2%) | 16 (4.8%) | 6 (5.7%) | 3 (18%) | 4 (11%) | ||
CIMP status | <0.0001 | 0.014 | |||||||
CIMP-negative | 521 (44%) | 311 (44%) | 210 (44%) | 139 (44%) | 37 (36%) | 8 (50%) | 19 (54%) | ||
CIMP-low | 460 (39%) | 224 (32%) | 236 (49%) | 154 (49%) | 59 (57%) | 4 (25%) | 16 (46%) | ||
CIMP-high | 206 (17%) | 172 (24%) | 34 (7%) | 21 (7%) | 7 (7%) | 4 (25%) | 0 | ||
PIK3CA mutation status | <0.0001 | 0.63 | |||||||
Wild-type | 983 (84%) | 632 (89%) | 351 (76%) | 242 (78%) | 72 (74%) | 12 (80%) | 19 (68%) | ||
Mutant | 190 (16%) | 78 (11%) | 112 (24%) | 70 (22%) | 25 (26%) | 3 (20%) | 9 (32%) | ||
BRAF mutation status | <0.0001 | 0.25 | |||||||
Wild-type | 1078 (85%) | 582 (77%) | 496 (99%) | 328 (99%) | 106 (98%) | 16 (94%) | 35 (100%) | ||
Mutant | 184 (15%) | 177 (23%) | 7 (1%) | 3 (1%) | 2 (2%) | 1 (6%) | 0 | ||
Mean LINE-1 methylation level (%) ± SD | 62.7 ± 9.3 | 62.8 ± 9.6 | 62.5 ± 9.0 | 0.33 | 62.7 ± 9.2 | 61.5 ± 8.2 | 64.2 ± 10.1 | 63.1 ± 9.0 | 0.42 |
KRAS mutation status and patient survival in BRAF-wild-type cases
KRAS
| Total No. | Colorectal cancer-specific mortality | Overall mortality | ||||
---|---|---|---|---|---|---|---|
No. of events | Univariate HR (95% CI) | Multivariate stage-stratified HR (95% CI) | No. of events | Univariate HR (95% CI) | Multivariate stage-stratified HR (95% CI) | ||
Wild-type (codons 12, 13, 61 and 146) | 582 | 144 | 1 (referent) | 1 (referent) | 258 | 1 (referent) | 1 (referent) |
All mutants together | 485 | 163 | 1.46 (1.17-1.83) | 1.19 (0.94-1.51) | 256 | 1.32 (1.11-1.57) | 1.14 (0.95-1.38) |
P = 0.0009 | P = 0.0018 | ||||||
Codons 12 and 13, and codons 61 and 146 | |||||||
Codons 12 and 13 | 434 | 151 | 1.51 (1.20-1.90) | 1.27 (0.99-1.62) | 235 | 1.36 (1.14-1.62) | 1.15 (0.95-1.40) |
P = 0.0004 | P = 0.0007 | ||||||
Codons 61 and 146 | 51 | 12 | 1.02 (0.57-1.85) | 0.85 (0.47-1.56) | 21 | 1.00 (0.64-1.56) | 1.07 (0.68-1.68) |
Codons 12, 13, 61 and 146 | |||||||
Codon 12 mutants | 328 | 121 | 1.64 (1.29-2.09) | 1.45 (1.12-1.87) | 183 | 1.45 (1.20-1.76) | 1.24 (1.01-1.52) |
P < 0.0001 | P = 0.0048 | P = 0.0001 | P = 0.037 | ||||
Codon 13 mutants | 106 | 30 | 1.16 (0.78-1.72) | 0.83 (0.55-1.25) | 52 | 1.11 (0.82-1.49) | 0.90 (0.66-1.24) |
Codon 61 mutants | 16 | 4 | 1.11 (0.41-3.01) | 0.81 (0.29-2.26) | 8 | 1.43 (0.71-2.90) | 1.55 (0.75-3.18) |
Codon 146 mutants | 35 | 8 | 0.98 (0.48-2.01) | 0.86 (0.42-1.78) | 13 | 0.84 (0.48-1.48) | 0.88 (0.50-1.56) |
The 10 most common mutations in codons 12, 13, 61 and 146 | |||||||
c.34G>A (p.G12S) | 12 | 6 | 2.44 (1.07-5.54) | 0.94 (0.39-2.23) | 7 | 1.57 (0.74-3.33) | 0.77 (0.35-1.70) |
P = 0.033 | |||||||
c.34G>C (p.G12R) | 7 | 5 | 5.25 (2.13-12.9) | 3.44 (1.25-9.43) | 6 | 4.69 (2.06-10.6) | 3.51 (1.42-8.70) |
P = 0.0003 | P = 0.017 | P = 0.0002 | P = 0.0067 | ||||
c.34G>T (p.G12C) | 42 | 16 | 1.70 (1.01-2.86) | 2.33 (1.36-3.99) | 25 | 1.56 (1.03-2.35) | 1.57 (1.02-2.42) |
P = 0.044 | P = 0.0021 | P = 0.035 | P = 0.039 | ||||
c.35G>A (p.G12D) | 155 | 51 | 1.46 (1.06-2.01) | 1.18 (0.84-1.66) | 80 | 1.37 (1.06-1.76) | 1.16 (0.89-1.51) |
P = 0.021 | P = 0.015 | ||||||
c.35G>C (p.G12A) | 19 | 6 | 1.28 (0.56-2.90) | 0.61 (0.26-1.42) | 9 | 1.00 (0.51-1.95) | 0.59 (0.30-1.17) |
c.35G>T (p.G12V) | 92 | 37 | 1.76 (1.22-2.52) | 2.13 (1.47-3.09) | 56 | 1.54 (1.16-2.06) | 1.54 (1.14-2.08) |
P = 0.0024 | P < 0.0001 | P = 0.0033 | P = 0.0048 | ||||
c.38G>A (p.G13D) | 101 | 30 | 1.23 (0.83-1.82) | 0.83 (0.55-1.26) | 50 | 1.14 (0.84-1.54) | 0.91 (0.66-1.25) |
c.183A>C (p.Q61H) | 7 | 2 | 1.06 (0.26-4.28) | 0.46 (0.11-1.93) | 4 | 1.28 (0.48-3.45) | 1.16 (0.42-3.18) |
c.436G>A (p.A146T) | 21 | 3 | 0.55 (0.17-1.71) | 0.50 (0.16-1.59) | 5 | 0.45 (0.19-1.10) | 0.51 (0.21-1.26) |
c.437C>T (p.A146V) | 11 | 4 | 1.94 (0.72-5.26) | 1.77 (0.64-4.90) | 7 | 2.02 (0.95-4.29) | 2.10 (0.97-4.56) |