Authors
Mohamed E. Salem, Scott Kopetz, Josep Tabernero, Frank A. Sinicrope, Myriam Chalabi, Jeanne Tie, Kunal C. Kadakia, Thomas J. George, Elizabeth Mauer, Lisa Macera, Calvin Y. Chao, Sara Lonardi, Eric Van Cutsem, Thierry Andre, Michael J. Overman
Background: The recent development of KRAS G12C inhibitors underscores the potential to target KRAS mutations. Right-sided and left-sided colon tumors (RT and LT) exhibit different molecular features. We characterize the prevalence of KRAS-variants, interrelation with primary tumor location, and association with immune biomarkers in CRC.
Methods: We retrospectively reviewed CRC tumors of all stages (with known sidedness) that underwent NGS with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Bivariate analyses were performed to compare KRAS alterations, immune biomarkers, and co-mutations by tumor location. P-values comparing individual co-mutations between groups were adjusted for false discovery (FDR).
Results: A total of 3,391 CRC were analyzed (RT: n = 442 [13%], transverse: n = 116 [3%], LT; n = 2,833 [84%]) of which 1486 (44%) tumors harbored KRAS mutations. Overall, KRAS mutations were more frequent in RT compared to transverse tumors and LT (52% vs 41% vs 43%, p<0.001, respectively). The most frequent KRAS mutation variants observed were G12D (29 %), G12V (22%), G13D (16%), and G12C (5.7%). There was no significant difference in the prevalence of KRAS variant types between LT and RT (p=0.5). Significant differences in genomic co-mutations with various KRAS variants were observed in the following genes: TP53, FBXW7, and NF1 (FDR-P<0.05). RT and transverse tumors were more likely have MSI-H and TMB-H (>10 mut/mb) status than LT (MSI-H: 18% vs 22% vs 2.2% and TMB-H (20% vs 22% vs 3%, P<0.001), respectively. CRC tumors harboring G13D variants were more likely to be associated with and MSI-H and TMB-H status (and 7.7% and 8.5%) compared to G12D (2.8 % and 3.9 %), G12V (1.8 % and 2.1%), and G12C (0% and 2.4%); P = 0.003 and 0.001.
Conclusions: The most frequent KRAS mutation variants observed in CRC tumors were G12D, G12V, G13D, and G12C. There was no significant difference in the prevalence of KRAS variant types between tumors of the left vs right colon. CRC tumors that harbored G13D variants were significantly more likely to be associated with MSI-H and TMB-H status.
List of selected co-mutated genes between KRAS-alteration groups.
|
G12A
N = 4311 |
G12C
N = 851 |
G12V
N = 3281 |
G13A
N = 2341 |
p-value2 |
q-value3 |
| TP53 |
279 (65%) |
60 (71%) |
224 (68%) |
171 (73%) |
0.002 |
0.035 |
| FBXW7 |
61 (14%) |
13 (15%) |
30 (9.1%) |
47 (20%) |
0.002 |
0.035 |
| NF1 |
10 (2.3%) |
1 (1.2%) |
2 (0.6%) |
4 (1.7%) |
<0.001 |
0.028 |
| NKX2-1 |
16 (3.7%) |
9 (11%) |
17 (5.2%) |
8 (3.4%) |
0.027 |
0.14 |
| ARID1A |
28 (6.5%) |
3 (3.5%) |
10 (3%) |
24 (10%) |
0.009 |
0.10 |
| PTEN |
22 (5.1%) |
7 (8.2%) |
23 (7%) |
10 (4.3%) |
0.035 |
0.14 |
| DPYD |
24 (5.6%) |
8 (9.4%) |
11 (3.4%) |
4 (1.7%) |
0.017 |
0.13 |
| PAX3 |
9 (2.1%) |
8 (9.4%) |
12 (3.7%) |
4 (1.7%) |
0.011 |
0.10 |
| ATM |
16 (3.7%) |
3 (3.5%) |
23 (7%) |
19 (8.1%) |
0.035 |
0.14 |
| EGFR |
29 (6.7%) |
3 (3.5%) |
12 (3.7%) |
4 (1.7%) |
0.039 |
0.15 |
| CDKN2B |
14 (3.2%) |
1 (1.2%) |
7 (2.1%) |
8 (3.4%) |
0.043 |
0.15 |
1n (%); 2Pearson’s Chi-squared test; Fisher’s exact test; 3 FDR correction for multiple testing.
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