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. 2023 Oct 31;19(6):104.
doi: 10.3892/br.2023.1686. eCollection 2023 Dec.

Association of KRAS, NRAS, BRAF and PIK3CA gene mutations with clinicopathological features, prognosis and ring finger protein 215 expression in patients with colorectal cancer

Jing-Bo Wu  1 , Xiao-Jing Li  1 , Hui Liu  1 , Yong-Juan Liu  1 , Xiu-Ping Liu  2
Affiliations

Association of KRAS, NRAS, BRAF and PIK3CA gene mutations with clinicopathological features, prognosis and ring finger protein 215 expression in patients with colorectal cancer

Jing-Bo Wu et al. Biomed Rep. .

Abstract

The relationships of KRAS, NRAS, BRAF and PIK3CA gene mutations with the clinicopathological features and prognosis of colorectal cancer (CRC) in patient are lacking. Furthermore, the role of ring finger protein 215 (RNF215) in CRC patients with KRAS, NRAS, BRAF and PIK3CA mutations remains unclear. In the present study, 182 surgical resection specimens from patients with primary CRC for retrospective analysis, were collected. KRAS/NRAS/BRAF/PIK3CA gene mutations were confirmed by an amplification-refractory mutation system. Immunohistochemistry (IHC) was conducted to confirm KRAS, NRAS, BRAF and PIK3CA protein expression. RNF215 expression in patients with CRC was evaluated using TIMER 2.0 database and IHC. The individual mutation rates of KRAS, NRAS, BRAF and PIK3CA were 40.7% (74/182), 4.4% (8/182), 4.4% (8/182) and 3.3% (6/182), respectively. The KRAS exon 2 mutation rate was the highest (61.5%, 64/104), and these mutations mainly occurred at codons 12 and 13. KRAS/NRAS/BRAF/PIK3CA wild-type CRC patients had significantly longer overall survival and disease-free survival than mutated KRAS/NRAS/BRAF/PIK3CA CRC patients (P<0.05). Overall, 45.4% (5/11) of patients with PIK3CA mutations had concomitant KRAS mutations. The KRAS/NRAS/BRAF/PIK3CA gene mutation rate in patients with lymph node metastasis (76.1%, 35/46) was significantly higher than that in patients without lymph node metastasis (50.8%, 69/136) (P=0.0027). There were no significant differences in IHC expression between patients with and without KRAS, NRAS, BRAF and PIK3CA mutations (P>0.05). The TIMER 2.0 analysis showed that RNF215 expression was significantly higher in the mutated BRAF group than in the wild-type BRAF group in CRC (P<0.05). In conclusion, KRAS is the most commonly mutated gene, and KRAS mutations may be a poor prognostic factor for patients with CRC. KRAS wild-type patient resistance may be related to PIK3CA gene mutations, although this needs further verification in larger cohorts. BRAF mutations may be associated with RNF215 expression in patients with CRC.

Keywords: BRAF; KRAS; NRAS proto-oncogene; PIK3CA; colorectal cancer; prognosis; ring finger protein 215.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
PCR mutation curves for the KRAS, NRAS, BRAF and PIK3CA genes in patients with colorectal cancer. (A) KRAS-EXON2-G13D mutation. (B) NRAS-EXON2-G12 mutation. (C) BRAF-EXON15 mutation. (D) PIK3CA-EXON10 mutation. (E) Concomitant KRAS-EXON2 and NRAS-EXON2 mutations. (F) Concomitant KRAS-EXON3 and PIK3CA-EXON10 mutations.
Figure 2
Figure 2
Analysis of concomitant mutations in KRAS, NRAS, BRAF and PIK3CA. (A) Venn diagram showing the distribution of single and concomitant mutations in the KRAS, NRAS, BRAF and PIK3CA genes. (B) Frequency of mutations in KRAS, NRAS, BRAF and PIK3CA exons in patients with CRC. The mutations in all exons are listed in the figure. Among them, the frequency of KRAS exon 2 mutations was the highest (55.8%), and concomitant mutations accounted for 7.7% (8/104) of mutations.
Figure 3
Figure 3
Kaplan-Meier curves for patients with colorectal cancer with and without KRAS mutations. (A) Comparison of overall survival, showing a significant difference (P=0.0246). (B) Comparison of disease-free survival, showing a significant difference (P=0.0016). HR, hazard ratio.
Figure 4
Figure 4
Typical IHC images of KRAS, NRAS, BRAF and PIK3CA staining in samples from patients with colorectal cancer observed under a light microscope. The brown-yellow particles of the cytoplasm indicate positive staining. (A) Positive expression of KRAS on IHC. (B) Negative expression of KRAS on IHC. (C) Positive expression of NRAS on IHC. (D) Negative expression of NRAS on IHC. (E) Positive expression of BRAF on IHC. (F) Negative expression of BRAF on IHC. (G) Positive expression of PIK3CA on IHC. (H) Negative expression of PIK3CA on IHC. IHC, immunohistochemistry.
Figure 5
Figure 5
Comparison of RNF215 expression in the KRAS, NRAS, BRAF and PIK3CA mutant vs. WT colorectal cancer groups via the TIMER 2.0 database. (A) Expression of RNF215 in KRAS mutant vs. WT colon cancer (P=0.84). (B) Expression of RNF215 in KRAS mutant vs. WT rectal cancer (P=0.081). (C) Expression of RNF215 in NRAS mutant vs. WT colon cancer (P=0.79). (D) Expression of RNF215 in NRAS mutant vs. WT rectal cancer (P=0.12). (E) Expression of RNF215 in BRAF mutant vs. WT colon cancer (P=0.0017). (F) Expression of RNF215 in BRAF mutant vs. WT rectal cancer (P=0.019). (G) Expression of RNF215 in PIK3CA mutant vs. WT colon cancer (P=0.88). (H) Expression of RNF215 in PIK3CA mutant vs. WT rectal cancer (P=0.37). RNF215, ring finger protein 215; WT, wild-type.
Figure 6
Figure 6
Comparison of RNF215 expression in the KRAS, NRAS, BRAF and PIK3CA mutant vs. WT CRC groups in 182 CRC patients. (A) Expression of RNF215 in KRAS mutant vs. WT CRC patients (P=0.8345). (B) Expression of RNF215 in NRAS mutant vs. WT CRC patients (P>0.9999). (C) Expression of RNF215 in BRAF mutant vs. WT CRC patients (P=0.4950). (D) Expression of RNF215 in PK3CA mutant vs. WT CRC patients (P>0.9999). RNF215, ring finger protein 215; CRC, colorectal cancer; WT, wild-type.
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Grants and funding

Funding: The present study was supported by the High-level Professional Physician Training Program of Minhang, Shanghai (grand no. 2020MZYS10) and the Natural Science Research Project of the Science and Technology Commission in Minhang, Shanghai (grand no. 2022MHZ043).

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