KRAS/NRAS Mutations Associated with Distant Metastasis and BRAF/PIK3CA Mutations Associated with Poor Tumor Differentiation in Colorectal Cancer

Figures & data

Table 1 Baseline Characteristics of CRC Patients

	Colorectal Cancer (n=408)
Gender
Male, n (%)	256(62.7%)
Female, n (%)	152(37.3%)
Age
<60, n (%)	185(45.3%)
≥60, n (%)	223(54.7%)
Tumor site
Colon	227(55.6%)
Rectum	175(42.9%)
Cecum	6(1.5%)
Maximum diameter of tumor
<5cm, n (%)	255(62.5%)
≥5cm, n (%)	138(33.8%)
Unknown, n (%)	15(3.7%)
Tumor differentiation
Well, n (%)	4(1.0%)
Moderate, n (%)	370(90.7%)
Poor, n (%)	34(8.3%)
Lymphovascular invasion
Present, n (%)	80(19.6%)
Absent, n (%)	328(80.4%)
Perineural invasion
Present, n (%)	54(13.2%)
Absent, n (%)	354(86.8%)
Disease stage at diagnosis
I-III, n (%)	317(77.7%)
IV, n (%)	91(22.3%)
MMR
pMMR, n (%)	380(93.1%)
dMMR, n (%)	15(3.7%)
Unknown, n (%)	13(3.2%)

Abbreviation: MMR, mismatch repair.

Table 2 Frequency and Composition Ratio of KRAS/NRAS/BRAF/PIK3CA Mutation in CRC Patients

Gene Name	Exon	Number and Frequency of Mutation (n,%)	Composition Ratio of Mutations
KRAS	Exon2	135(33.1%)	62.5%
	Exon3	11(2.7%)	5.1%
	Exon4	15(3.7%)	6.9%
NRAS	Exon2	7(1.7%)	3.2%
	Exon3	3(0.7%)	1.4%
BRAF	Exon15	9(2.2%)	4.2%
PIK3CA	Exon9	6(1.5%)	2.8%
	Exon20	1(0.2%)	0.5%
KRAS and NRAS	KRAS exon2 and NRAS exon2	1(0.2%)	0.5%
KRAS and BRAF	KRAS exon2 and BRAF exon15	1(0.2%)	0.5%
KRAS and PIK3CA	KRAS exon2 and PIK3CA exon9	17(4.2%)	7.9%
	KRAS exon2 and PIK3CA exon20	8(2.0%)	3.7%
	KRAS exon3 and PIK3CA exon9	1(0.2%)	0.5%
	KRAS exon3 and PIK3CA exon20	1(0.2%)	0.5%
Total		216(52.9%)	100.0%

Table 3 Clinicopathological Characteristics According to KRAS/NRAS/BRAF/PIK3CA Gene Mutation Status in CRC Patients

	KRAS (Exon2/3/4)			NRAS (exon2/3)			BRAF (Exon15)			PIK3CA (Exon9/20)
	Normal (n=218)	Mutated (n=190)	P value	Normal (n=397)	Mutated (n=11)	P value	Normal (n=398)	Mutated (n=10)	P value	Normal (n=374)	Mutated (n=34)	P value
Gender
Male	144	112	0.151	249	7	1.000	251	5	0.510	240	16	0.063
Female	74	78		148	4		147	5		134	18
Age
<60	97	88	0.765	179	6	0.556	180	5	0.761	173	12	0.281
≥60	121	102		218	5		218	5		201	22
Tumor site
Colon	117	110	0.682	223	4	0.340	219	8	0.309	208	19	1.000
Rectum	98	77		168	7		173	2		160	15
Cecum	3	3		6	0		6	0		6	0
Maximum diameter of tumor
<5cm	135	120	0.916	248	7	1.000	251	4	0.288	232	23	0.851
≥5cm	72	66		135	3		133	5		127	11
Tumor differentiation
Well	1	3	0.388	3	1	0.112	4	0	0.012	4	0	0.121
Moderate	201	169		360	10		364	6		342	28
Poor	16	18		34	0		30	4		28	6
Lymphovascular invasion
Present	43	37	1.000	80	0	0.132	75	5	0.029	73	7	0.824
Absent	175	153		317	11		323	5		301	27
Perineural invasion
Present	25	29	0.306	54	0	0.373	52	2	0.628	52	2	0.288
Absent	193	161		343	11		346	8		322	32
Disease stage at diagnosis
I-III	178	139	0.043	310	7	0.273	310	7	0.699	288	29	0.294
IV	40	51		87	4		88	3		86	5
Lymph node metastasis
No	104	73	0.071	175	2	0.124	174	3	0.524	164	13	0.590
Yes	114	117		222	9		224	7		210	21
Distant metastasis
No	179	138	0.024	310	7	0.273	310	7	0.699	288	29	0.294
Yes	39	52		87	4		88	3		86	5
MMR
pMMR	200	180	1.000	370	10	1.000	371	9	1.000	350	30	0.121
dMMR	8	7		15	0		15	0		12	3

Note: Bold values for P<0.05.

Table 4 Multivariate Logistic Regression in CRC Patients Between Gene Mutations and Clinicopathological Characteristics

Characteristics	KRAS			NRAS			BRAF			PIK3CA
	Adjusted Odds Ratio (95% CI)	R^2	P value	Adjusted Odds Ratio (95% CI)	R^2	P value	Adjusted Odds Ratio (95% CI)	R^2	P value	Adjusted Odds Ratio (95% CI)	R^2	P value
Gender (Male/Female)	0.691(0.450–1.061)	0.154	0.091	2.252(0.425–11.947)	0.164	0.340	0.555(0.120–2.562)	0.250	0.450	0.443(0.210–0.934)	0.181	0.032
Age (≥60/<60)	0.915(0.605–1.383)		0.673	0.956(0.241–3.799)		0.950	0.778(0.157–3.856)		0.759	1.723(0.798–3.720)		0.166
Tumor site (Colon/Other)	1.191(0.769–1.845)		0.434	0.298(0.065–1.362)		0.119	3.325(0.346–31.990)		0.298	1.093(0.496–2.407)		0.825
Maximum diameter of tumor (≥5cm/<5cm)	0.992(0.633–1.555)		0.971	1.325(0.294–5.969)		0.714	2.362(0.476–11.727)		0.293	0.896(0.394–2.035)		0.792
Tumor differentiation (Poor/Moderate+well)	1.646(0.729–3.717)		0.231	–		0.998	7.224(1.356–38.488)		0.021	3.811(1.268–11.455)		0.017
Lymphovascular invasion (Present/Absent)	0.745(0.423–1.314)		0.310	–		0.997	4.547(0.874–23.666)		0.072	0.968(0.365–2.567)		0.948
Perineural invasion (Present/Absent)	1.897(0.962–3.738)		0.064	–		0.997	0.553(0.054–5.640)		0.617	0.387(0.083–1.808)		0.227
Distant metastasis (Yes/No)	1.675(1.017–2.760)		0.043	5.183(1.239–21.687)		0.024	0.495(0.075–3.265)		0.465	0.512(0.184–1.428)		0.201

Notes: P< 0.05 was considered statistically significant. Bold values for P<0.05.

Abbreviation: CI, confidence interval.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.