Colorectal cancer tumor phenotypes associated with KRAS, NRAS, and BRAF hot-spot mutations

doi:10.4291/wjgp.v16.i3.107954

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World Journal of Gastrointestinal Pathophysiology

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Retrospective Cohort Study

World J Gastrointest Pathophysiol. Sep 22, 2025; 16(3): 107954
Published online Sep 22, 2025. doi: 10.4291/wjgp.v16.i3.107954

Table 1 Baseline characteristics of the study cohort (n = 799)

Characteristics	Number of patients	Percentage
Age at diagnosis
mean ± SD	61.8 ± 12.8	N/A
Median, IQR	62-16.5	N/A
Sex
Male	533	66.7
Female	266	33.3
Race/ethnicity
White	439	54.9
Black	167	20.9
Hispanic	175	21.9
Other	18	2.3
NM_004985.5 (KRAS) mutations
Wildtype	483	60.5
c.35G>A (p.Gly12Asp)	108	13.4
c.35G>T (p.Gly12Val)	72	9.0
c.34G>T (p.Gly12Cys)	25	3.1
Other p.Gly12 mutations	31	3.9
c.38G>A (p.Gly13Asp)	62	7.8
p.Gln61 mutations	18	2.3
NM_002524.5 (NRAS) mutations
Wildtype	738	92.3
p.Gln61 mutations	21	2.7
Other mutations	13	1.7
Unknown	27	3.3
NM_004333.6 (BRAF) mutations
Wildtype	746	93.4
c.1799T>A (p.Val600Glu)	48	6.0
Unknown	5	0.6
DNA MMR
MMR-proficient	709	88.6
MMR-deficient	84	10.5
Unknown	6	0.9
Primary tumor site
Right colon	244	30.5
Transverse colon	51	6.4
Left colon	281	35.2
Rectum	223	27.9
Familial risk
No	455	56.9
Yes	344	43.1
Tobacco use
No	296	37.0
Yes	503	63.0
Number of comorbidities
0	146	18.3
1 or 2	357	44.7
3 or more	296	37.0

BRAF: V-raf murine sarcoma viral oncogene homolog B1; KRAS: Kirsten rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma RAS viral oncogene homolog; CI: Confidence interval; OR: Odds ratio; MMR: Mismatch repair; IQR: Interquartile range; N/A: Not applicable.

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Table 2 Gene mutations according to colorectal cancer tumor specimens sources (n = 799), n (%)

Specimen source	Total	Wildtype	KRAS mutation	NRAS mutation	BRAF mutation
Primary tumor tissue	722 (90.3)	376 (92.1)	270 (85.4)	32 (94.1)	44 (91.6)
Metastatic tumor tissue	77 (9.7)	32 (7.9)	46 (14.6)	2 (5.9)	4 (8.4)

BRAF: V-raf murine sarcoma viral oncogene homolog B1; KRAS: Kirsten rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma RAS viral oncogene homolog.

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Table 3 Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog, and v-raf murine sarcoma viral oncogene homolog B1 mutations by pathological stage in patients with colorectal cancer patients (n = 799), n (%)

Protein change	Nucleotide change	Overall	pT1	pT2	pT3	pT4	Unknown
Protein change	Nucleotide change	Overall	65 (8.1)	102 (12.8)	344 (43.1)	257 (32.2)	31 (3.8)
NM_004985.5 (KRAS) hot-spot mutations
KRAS wildtype	N/A	483 (60.5)	43 (8.8)	57 (11.8)	228 (47.1)	133 (27.5)	23 (4.8)
KRAS codon 12
p.Gly12Asp (G12D)	c.35G>A	108 (13.5)	6 (5.6)	17 (15.7)	46 (42.6)	35 (32.4)	4 (3.7)
p.Gly12Val (G12V)	c.35G>T	72 (9.0)	5 (6.9)	8 (11.1)	25 (34.7)	33 (45.8)	1 (1.5)
p.Gly12Cys (G12C)	c.34G>T	25 (3.1)	2 (8.0)	4 (16.0)	10 (40.0)	9 (36.0)	0 (0.0)
p.Gly12Ser (G12S)	c.34G>A	18 (2.3)	3 (16.7)	3 (16.7)	7 (38.8)	5 (27.8)	0 (0.0)
p.Gly12Ala (G12A)	c.35G>C	8 (1.0)	1 (12.5)	1 (12.5)	2 (25.0)	3 (37.5)	1 (12.5)
p.Gly12Arg (G12R)	c.34G>C	5 (0.6)	0 (0.0)	2 (40.0)	0 (0.0)	4 (60.0)	0 (0.0)
KRAS codon 13
p.Gly13Asp (G13D)	c.38G>A	62 (7.7)	4 (6.4)	8 (12.8)	20 (32.3)	30 (48.5)	0 (0.0)
KRAS codon 61
p.Gln61His (Q61H)	c.183A>T	5 (0.6)	1 (20.0)	1 (20.0)	1 (20.0)	2 (40.0)	0 (0.0)
p.Gln61His (Q61H)	c.183A>C	6 (0.7)	1 (16.7)	0 (0.0)	1 (16.7)	3 (50.0)	1 (16.7)
p.Gln61Leu (Q61L)	c.182A>T	4 (0.5)	0 (0.0)	0 (0.0)	3 (75.0)	0 (0.0)	1 (25.0)
p.Gln61Arg (Q61R)	c.182A>G	3 (0.4)	0 (0.0)	1 (33.3)	1 (33.3)	1 (33.3)	0 (0.0)
p.Gln61Glu (Q61E)	c.181C>G	1 (0.1)	0 (0.0)	0 (0.0)	1 (100)	0 (0.0)	0 (0.0)
NM_002524.5 (NRAS) hot-spot mutations
NRAS wildtype	N/A	738 (92.3)	61 (8.3)	97 (13.2)	317 (42.8)	235 (31.8)	29 (3.9)
NRAS codon 12
p.Gly12Asp (G12D)	c.35G>A	6 (0.8)	0 (0.0)	0 (0.0)	3 (50.0)	2 (33.3)	1 (26.7)
p.Gly12Val (G12V)	c.35G>T	3 (0.4)	0 (0.0)	0 (0.0)	1 (33.3)	2 (66.7)	0 (0.0)
p.Gly12Cys (G12C)	c.34G>T	1 (0.1)	0 (0.0)	0 (0.0)	0 (0.0)	1 (100)	0 (0.0)
p.Gly12Ser (G12S)	c.34G>A	1 (0.1)	0 (0.0)	0 (0.0)	1 (100)	0 (0.0)	0 (0.0)
NRAS codon 13
p.Gly13Val (G13V)	c.38G>T	2 (0.3)	0 (0.0)	0 (0.0)	0 (0.0)	2 (100)	0 (0.0)
NRAS codon 61
p.Gln61Lys (Q61K)	c.181C>A	12 (1.5)	0 (0.0)	2 (16.7)	7 (58.3)	3 (25.0)	0 (0.0)
p.Gln61Arg (Q61R)	c.182A>G	6 (0.8)	1 (16.7)	0 (0.0)	3 (50.0)	2 (33.3)	0 (0.0)
p.Gln61His (Q61H)	c.183A>T	2 (0.3)	0 (0.0)	1 (50.0)	1 (50.0)	0 (0.0)	0 (0.0)
p.Gln61Leu (Q61L)	c.182A>T	1 (0.1)	0 (0.0)	0 (0.0)	0 (0.0)	1 (100)	0 (0.0)
Unknown NRAS	N/A	27 (3.3)	3 (11.1)	2 (7.4)	12 (44.5)	9 (33.3)	1 (3.7)
NM_004333.6 (BRAF) V600 mutations
BRAF V600 wildtype	N/A	746 (93.4)	62 (8.3)	99 (13.3)	318 (42.6)	238 (31.9)	29 (3.9)
p.Val600Glu (V600E)	c.1799T>A	48 (6.0)	3 (6.3)	3 (6.3)	25 (52.2)	15 (31.1)	2 (4.1)
Unknown BRAF	N/A	5 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)	1 (20.0)	4 (80.0)

BRAF: V-raf murine sarcoma viral oncogene homolog B1; KRAS: Kirsten rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma RAS viral oncogene homolog; pT: Pathological stage; N/A: Not applicable.

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Table 4 Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog, and v-raf murine sarcoma viral oncogene homolog B1 mutations by lymph node and distant metastases in patients with colorectal cancer (n = 799), n (%)

Protein change	Nucleotide change	Overall	+ pN	+ M
Protein change	Nucleotide change	Overall	380 (47.6)	298 (37.3)
NM_004985.5 (KRAS) hot-spot mutations
KRAS wildtype	N/A	483 (60.5)	231 (47.7)	155 (32.0)
KRAS codon 12
p.Gly12Asp (G12D)	c.35G>A	108 (13.5)	51 (47.2)	52 (48.1)
p.Gly12Val (G12V)	c.35G>T	72 (9.0)	39 (54.2)	38 (52.8)
p.Gly12Cys (G12C)	c.34G>T	25 (3.1)	15 (60.0)	13 (52.0)
p.Gly12Ser (G12S)	c.34G>A	18 (2.3)	5 (27.8)	7 (38.9)
p.Gly12Ala (G12A)	c.35G>C	8 (1.0)	2 (25.0)	2 (25.0)
p.Gly12Arg (G12R)	c.34G>C	5 (0.6)	2 (40.0)	3 (60.0)
KRAS codon 13
p.Gly13Asp (G13D)	c.38G>A	62 (7.7)	31 (50.0)	22 (35.5)
KRAS codon 61
p.Gln61His (Q61H)	c.183A>T	5 (0.6)	2 (40.0)	3 (60.0)
p.Gln61His (Q61H)	c.183A>C	6 (0.7)	2 (33.3)	4 (66.7)
p.Gln61Leu (Q61L)	c.182A>T	4 (0.5)	0 (0.0)	0 (0.0)
p.Gln61Arg (Q61R)	c.182A>G	3 (0.4)	0 (0.0)	0 (0.0)
p.Gln61Glu (Q61E)	c.181C>G	1 (0.1)	0 (0.0)	1 (100.0)
NM_002524.5 (NRAS) hot-spot mutations
NRAS wildtype	N/A	738 (92.3)	352 (47.7)	271 (36.7)
NRAS codon 12
p.Gly12Asp (G12D)	c.35G>A	6 (0.8)	2 (33.3)	3 (50.0)
p.Gly12Val (G12V)	c.35G>T	3 (0.4)	1 (33.3)	1 (33.3)
p.Gly12Cys (G12C)	c.34G>T	1 (0.1)	0 (0.0)	1 (100.0)
p.Gly12Ser (G12S)	c.34G>A	1 (0.1)	0 (0.0)	1 (100.0)
NRAS codon 13
p.Gly13Val (G13V)	c.38G>T	2 (0.3)	2 (100.0)	1 (50.0)
NRAS codon 61
p.Gln61Lys (Q61K)	c.181C>A	12 (1.5)	8 (66.6)	5 (41.7)
p.Gln61Arg (Q61R)	c.182A>G	6 (0.8)	3 (50.0)	2 (33.3)
p.Gln61His (Q61H)	c.183A>T	2 (0.3)	1 (50.0)	0 (0.0)
p.Gln61Leu (Q61L)	c.182A>T	1 (0.1)	0 (0.0)	0 (0.0)
Unknown NRAS	N/A	27 (3.3)	11 (40.7)	13 (48.1)
NM_004333.6 (BRAF) V600 mutations
BRAF V600 wildtype	N/A	746 (93.4)	349 (46.8)	278 (37.3)
p.Val600Glu (V600E)	c.1799T>A	48 (6.0)	28 (58.3)	15 (31.2)
Unknown BRAF	N/A	5 (0.6)	3 (60.0)	5 (100.0)

BRAF: V-raf murine sarcoma viral oncogene homolog B1; KRAS: Kirsten rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma RAS viral oncogene homolog; M: Distant metastasis; pN: Lymph node metastasis; N/A: Not applicable.

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Citation: Abdelgadir O, Kuo YF, Khan MF, Okorodudu AO, Cheng YWO, Dong J. Colorectal cancer tumor phenotypes associated with KRAS, NRAS, and BRAF hot-spot mutations. World J Gastrointest Pathophysiol 2025; 16(3): 107954
URL: https://www.wjgnet.com/2150-5330/full/v16/i3/107954.htm
DOI: https://dx.doi.org/10.4291/wjgp.v16.i3.107954