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 [DOI: 10.4291/wjgp.v16.i3.107954]
Corresponding Author of This Article
Jianli Dong, MD, PhD, Professor, Department of Pathology, Director, Molecular Diagnostics Division, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States. jidong@utmb.edu
Research Domain of This Article
Oncology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Abdelgadir OA and Dong J designed the research study; Abdelgadir O, Kuo YF, and Dong J performed and validate the statistical analysis; Abdelgadir O, Kuo YF, Khan MF, Okorodudu AO, Cheng YWO, and Dong J performed the manuscript writing, review and editing; and all authors have read and agreed to the published version of the manuscript.
Institutional review board statement: This study was approved by the Medical Ethics Committee of University of Texas Medical Branch, approval No. 02-089.
Informed consent statement: No patient informed consent specific to this study was required due to the retrospective nature of the study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The data presented in this study are de-identified and available upon reasonable request from the corresponding author. The data are not publicly available due to patient confidentiality restrictions.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jianli Dong, MD, PhD, Professor, Department of Pathology, Director, Molecular Diagnostics Division, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States. jidong@utmb.edu
Received: April 2, 2025 Revised: May 19, 2025 Accepted: August 1, 2025 Published online: September 22, 2025 Processing time: 171 Days and 15.1 Hours
Abstract
BACKGROUND
Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) nucleotide variants may generate quantitatively or qualitatively various protein activities, which may be reflected in their differential association with tumor characteristics.
AIM
To examine the association between these mutations and colorectal cancer (CRC) progression stages.
METHODS
A retrospective analysis was conducted on 799 patients with CRC, whose tumor samples were examined for mutations in the hot-spots of the KRAS, NRAS, and BRAF genes at the University of Texas Medical Branch, spanning from January 2016 to July 2023. Statistical analyses were performed to assess the association of specific nucleotide changes with tumor, nodes, and metastasis stages.
RESULTS
KRAS mutations were found in 39.5% of cases, NRAS mutations in 4.4%, and BRAF mutations in 6.0%. The KRAS p.Gly12Val and p.Gly13Asp mutations were positively associated with pathological stage 4 tumors. Additionally, the KRAS p.Gly12Asp and p.Gly12Val mutations were linked to an increased risk of distant metastasis. Meanwhile, the BRAF Val600Glu mutation was associated with a higher likelihood of lymph node involvement.
CONCLUSION
Our findings support the potential prognostic utility of specific KRAS (p.Gly12Val, p.Gly12Asp, and p.Gly13Asp) and BRAF p.Val600Glu mutations in CRC. These results are preliminary and require validation through larger, multi-center studies before they can be considered reliable in clinical practice.
Core Tip: In colorectal cancer, the kirsten rat sarcoma viral oncogene homolog p.Gly12Val and p.Gly13Asp mutations were linked to advanced tumor stage, while the kirsten rat sarcoma viral oncogene homolog p.Gly12Asp and p.Gly12Val mutations showed a positive association with distant metastasis. The v-raf murine sarcoma viral oncogene homolog B1 p.Val600Glu mutation was associated with lymph node metastasis. This study provides evidence to support the prognostic and risk stratification potential of these mutations. Further studies are needed to validate these findings and explore their clinical implications for patients with colorectal cancer.
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
Colorectal cancer (CRC) poses a significant public health challenge. In the United States, CRC is the third leading cause of cancer-related deaths in men and the fourth in women. According to 2025 projections, approximately 154270 new cases and 52900 deaths are anticipated[1]. CRC develops through a multi-stage process of accumulating genetic alterations, progressing from adenomas to invasive adenocarcinoma. The malignant transformation of colonic epithelium can be a protracted process, spanning over a decade or more[2,3].
Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, with varying protein activities, can drive distinct tumor phenotypes[4]. These genes regulate key cellular processes (proliferation, motility, survival) via the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase pathway[3,5]. Oncogenic mutations in these genes can lead to uncontrolled proliferation and tumor growth[5,6]. The “seed and soil” hypothesis proposes that successful metastasis relies on a favorable interaction between the circulating tumor cells (the “seed”) and the microenvironment of the distant organ (the “soil”)[7]. In CRC, this concept underscores the importance of both the intrinsic properties of tumor cells, such as KRAS, NRAS, and BRAF mutations, as well as the microenvironmental factors of the local and remote metastatic sites in determining the metastatic potential and progression of the disease[8].
Anti-epidermal growth factor receptor (EGFR) therapy has been a key treatment for metastatic CRC (mCRC) for nearly two decades, with KRAS and NRAS mutational testing guiding its use in this patient population[9,10]. Current guidelines limit anti-EGFR monoclonal antibodies to patients with wildtype KRAS and NRAS, though their prognostic significance remains uncertain[11]. KRAS mutations are linked to poorer outcomes, but data are inconsistent, and NRAS mutations are too rare for definitive conclusions[9-11]. Consequently, KRAS and NRAS status are not routinely used for prognosis[11]. In contrast, the BRAF c.1799T>A (p.Val600Glu) mutation predicts poor response to anti-EGFR therapy unless combined with BRAF inhibitors and serves as a strong negative prognostic factor in mCRC[11-14]. However, cetuximab in first-line therapy may offer some benefit in this subgroup[15].
Emerging evidence suggests that the clinical and biological behavior of CRC is significantly influenced not just by the presence of KRAS, NRAS or BRAF mutations, but by the specific mutations subtype[4]. Amino acid substitutions in oncogenic proteins such as KRAS and BRAF significantly impact protein structure and function. This results in the continuous activation of the mitogen-activated protein kinase (MAPK)/ERK pathway, thereby driving tumorigenesis[16].
For instance, KRAS mutations like c.35G>T (p.Gly12Val) cause steric hindrance, while c.35G>A (p.Gly12Asp) and c.38G>A (p.Gly13Asp) disrupt electrostatic interactions, sustaining signaling[17-19]. Likewise, BRAF c.1799T>A (p.Val600Glu) alters kinase domain polarity, leading to aberrant activation[20,21]. These alterations often arise from transitions between polar and nonpolar residues, which can disrupt hydrogen bonding, compromise protein stability, and affect folding dynamics, depending on the mutation’s structural and functional relevance[4,22,23]. Although these mutations serve as fundamental drivers of tumorigenesis, tumor progression is further shaped by microenvironmental, stromal, and epigenetic influences[24].
Most studies categorize KRAS, NRAS, and BRAF mutations into two broad groups: Wildtype and mutant. However, this simplified classification does not account for the nuances and variations that arise from specific nucleotide alterations in these genes. As a result, the implications of these specific mutations remain under explored. Investigating the link between these mutations and adverse outcomes could help identify potential genetic markers of tumor behavior, which could contribute to improving CRC prognostication and risk assessment. To this end, this study investigates the relationship of specific hot-spot mutations in KRAS, NRAS, and BRAF with the CRC tumor phenotype [tumor-node-metastasis (TNM)] stages.
MATERIALS AND METHODS
Study population
This study retrospectively analyzed 799 patients with CRC treated at the University of Texas Medical Branch. Between January 2016 and July 2023, tumor samples from these patients underwent testing for mutations in the hot-spots of the KRAS, NRAS, and BRAF genes. Relevant clinical data were retrieved from the patient’s medical records. All data were anonymized after collection to safeguard patient confidentiality. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board at University of Texas Medical Branch, Galveston, Texas, approval No. 02-089 date: August 26, 2024. Due to the retrospective nature of this study, no patient informed consent specific to this study was required.
KRAS, NRAS, and BRAF mutational analysis
CRC tumor samples were analyzed for mutations in KRAS, NRAS, and BRAF genes. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissues using the QIAamp DNA formalin-fixed, paraffin-embedded Tissue Kit (Qiagen, Germantown, MD, United States), following the manufacturer’s instructions. Polymerase chain reaction amplification targeted specific regions of KRAS (codons 12, 13, and 61), NRAS (codons 12, 13, and 61), and BRAF (codon 600). Amplification conditions included an initial denaturation at 95 °C (15 minutes), followed by 42 cycles of denaturation at 95 °C (20 seconds), annealing at 53 °C (30 seconds), elongation at 72 °C (20 seconds), and final elongation (5 minutes). Polymerase chain reaction product quality was confirmed by agarose gel electrophoresis. Pyrosequencing on the PyroMark Q24 System was used for mutational analysis, following the manufacturer’s instructions. Further pyrosequencing and primers information are provided in the Supplementary Tables 1 and 2.
Measures
The study focused on several key outcomes, including the tumor pathological stage (pT) (pT1, pT2, pT3, pT4), lymph node (pN) metastasis (pN+), and distant metastasis (M). We assessed three main predictor variables: KRAS gene [grouped as wildtype, c.35G>A (p.Gly12Asp), c.35G>T (p.Gly12Val), c.34G>T (p.Gly12Cys), other p.Gly12 mutations, c.38G>A (p.Gly13Asp), and p.Gln61 mutations], NRAS gene (grouped as wildtype, p.Gln61 mutations, other mutations, or unknown), and BRAF gene (wildtype or c.1799T>A “p.Val600Glu”). Covariates such as age at diagnosis, biological sex, racial/ethnic group, primary tumor site, DNA mismatch repair (MMR), familial cancer risk, number of comorbidities, and tobacco use were included in multivariable analyses.
Statistical analysis
The data were processed using R software (version 4.3.1). The mutation distribution pattern was reported in frequency and proportion. Patient baseline characteristics were summarized using descriptive statistics. Categorical variables were reported as counts and percentages, whereas continuous variables were presented as both mean ± SD and medians with interquartile ranges. Cases with missing data for the pT stage (n = 31) were excluded from the pT stage regression models, and those missing BRAF status (n = 5) were excluded from all regression models. Multivariable logistic regressions were used to examine the association between KRAS, NRAS, and BRAF hot-spot mutations and TNM stages. Model fit was assessed using the Hosmer-Lemeshow test, and statistical significance was defined by a two-sided P < 0.05.
RESULTS
Baseline characteristics of the study cohort
Table 1 indicates the demographic and clinicopathological of the study cohort. The mean age of the study cohort was 61.8 ± 12.8 years, and the median age was 62 years (interquartile range 16.5). The cohort was predominantly male (66.7%) and primarily White (54.9%). KRAS mutations were detected in 39.5%, NRAS mutations in 4.4%, and BRAF mutations in 6% of CRC cases. While 88.6% of tumors were MMR-proficient, 10.5% were MMR-deficient. Left-sided colon was the most common primary tumor site (35.2%), followed by right-sided colon (30.5%), rectum (27.9%), and transverse colon (6.4%). Familial risk of CRC was present in 43.1% of patients, and tobacco use was reported in 63.0% of patients. Additionally, 44.7% of patients had one or two comorbidities, 37.0% had three or more, and 18.3% had none. Additional KRAS, NRAS, and BRAF mutations distribution by pT stages, pN and distant organ metastases visualized in the Supplementary Figures 1-3.
Table 1 Baseline characteristics of the study cohort (n = 799).
CRC tumor specimen sources and mutation frequencies
Of the total (n = 799) CRC specimens, 722 (90.3%) were obtained from primary tumors, and 77 (9.7%) were obtained from metastatic tumors. KRAS mutations were found in 270 primary tumor specimens, NRAS mutations in 32 specimens, and BRAF mutations in 44 specimens. Among the 77 metastatic tumor specimens, KRAS mutations were detected in 46 specimens, while NRAS mutations were found in 2 specimens and BRAF mutations in 4 specimens (Table 2).
Table 2 Gene mutations according to colorectal cancer tumor specimens sources (n = 799), n (%).
The purpose of this analysis was to investigate the distribution of KRAS, NRAS, and BRAF hot-spot mutations across different tumor pT stages in a cohort of 799 patients with CRC. The patient cohort was stratified by pT stages: 8.1% at pT1, 12.8% at pT2, 43.1% at pT3, and 32.2% at pT4. KRAS mutations were detected in 39.5% of cases, primarily as p.Gly12Asp (13.5%) and p.Gly12Val (9%). NRAS mutations were found in 4.4% of cases, predominantly as p.Gln61 Lys. BRAF p.Val600Glu was identified in 6% of cases. Notably, the majority of KRAS mutations (n = 316) were identified in pT4 tumors (125/316), whereas NRAS mutations (n = 34) were most frequently observed in pT3 tumors (16/34). Similarly, BRAF mutations (n = 48) were predominantly found in pT3 tumors (25/48) (Table 3).
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 (%).
This analysis aimed to examine the distribution of KRAS, NRAS, and BRAF hot-spot mutations according to regional pN and M in a cohort of 799 CRC patients. Of those, 47.6% had pN+, and 37.3% had M. Among the KRAS mutations, p.Gly12Cys had the greatest prevalence of pN+ (60%), followed by p.Gly12Val (54.2%) and p.Gly13Asp (50%). For NRAS mutations, patients with p.Gly13Val had the highest rate of pN+ (100%), followed by p.Gln61 Lys (66.6%). Patients with BRAF p.Val600Glu had a pN+ rate of 58.3% (Table 4).
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 (%).
KRAS, NRAS, and BRAF hot-spot mutations association with TNM stages in CRC
Figure 1 shows the relationship between KRAS, NRAS, and BRAF hotspot mutations and the pT of CRC tumors, as determined through multivariable logistic regression analysis. The KRAS p.Gly12Val mutation showed a positive association with a 40% reduced likelihood of pT3 CRC as opposed to the KRAS wildtype. The KRAS p.Gly13Asp and other p.Gly12 mutations were significantly associated with a decreased likelihood of pT3 CRC, with reductions of 50% and 60%, respectively. Conversely, the KRAS p.Gly12Val and p.Gly13Asp mutations were linked to a higher likelihood of pT4 CRC tumors, with increases of 110% and 130%, respectively, as opposed to KRAS wildtype.
Figure 1 Association of specific kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog, and v-raf murine sarcoma viral oncogene homolog B1 hot-spot mutations with tumor’s pathological stage.
A statistically significant at P < 0.05. Regression models were adjusted for age at diagnosis, sex, race/ethnicity, primary tumor site, DNA mismatch repair status, familial cancer risk, number of comorbidities, and tobacco use. BRAF: V-raf murine sarcoma viral oncogene homolog B1; KRAS: Kirsten rat sarcoma viral oncogene homolog; NC: Not calculated; NRAS: Neuroblastoma RAS viral oncogene homolog; CI: Confidence interval; OR: Odds ratio; pT: Pathological stage.
Figure 2 illustrates how specific hotspot mutations in KRAS, NRAS, and BRAF are associated with pN involvement and M, as determined through multivariable logistic regression analyses. The group of other KRAS p.Gly12 mutations was significantly associated with a 60% reduced likelihood of pN+ in CRC. Tumors with the BRAF p.Val600Glu mutation exhibited a 240% higher likelihood of developing pN+. The KRAS p.Gly12Asp and p.Gly12Val mutations showed positive associations with M, with increases of 120% and 130%, respectively.
Figure 2 Association of specific kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog, and v-raf murine sarcoma viral oncogene homolog B1 hot-spot mutations with regional lymph node and distant metastasis.
A statistically significant at P < 0.05. Regression models were adjusted for age at diagnosis, sex, race/ethnicity, primary tumor site, DNA mismatch repair status, familial cancer risk, number of comorbidities, and tobacco use. BRAF: V-raf murine sarcoma viral oncogene homolog B1; KRAS: Kirsten rat sarcoma viral oncogene homolog; NC: Not calculated; NRAS: Neuroblastoma RAS viral oncogene homolog; CI: Confidence interval; OR: Odds ratio.
DISCUSSION
In this retrospective study, we explored the association of distinct KRAS, NRAS, and BRAF hot-spot mutations with tumor phenotype, particularly in relation to TNM staging. We found that patients with KRAS p.Gly12Val and p.Gly13Asp mutations were more likely to develop advanced stage tumors (pT4) compared to those with the KRAS wildtype. Patients with the BRAF p.Val600Glu mutation were more likely to experience pN+. Similarly, patients with KRAS p.Gly12Asp and p.Gly12Val mutations had a higher likelihood of M.
While KRAS mutations are established predictors of treatment response and prognosis in mCRC, their role in localized disease (stages I-III) is less clear[9,11]. Research has focused on the metastatic setting due to KRAS’s importance in anti-EGFR therapy decisions, which are irrelevant in early-stage CRC. Consequently, guidelines do not typically recommend KRAS for prognostic assessment in this context[9,11]. KRAS mutations are highly prevalent in CRC (about 40%) and confer anti-EGFR resistance[11]. Our study found a significant association between the KRAS p.Gly12Val and p.Gly13Asp mutations and advanced CRC, specifically pT4 tumors. Although research on these specific KRAS mutations and pT4 disease is limited, our findings align with prior work linking codon 12/13 KRAS mutations to advanced-stage CRC[25-29]. The contrasting associations of specific KRAS p.Gly12Val and p.Gly13Asp mutations across pT3 and pT4 tumors likely reflect sample size-driven distributional effects, where increased representation in one subgroup (e.g., pT4) leads to a relative reduction in another (e.g., pT3), rather than indicating opposing biological mechanisms. This observation is particularly relevant when mutations are mutually exclusive and total mutation counts are constrained. However, larger studies are needed to determine whether true stage-specific patterns exist beyond these statistical shifts.
Preclinical data suggest the KRAS p.Gly12Val mutation has higher metastatic potential than p.Gly13Asp[16]. While some studies link KRAS codon 12/13 to M[30-35], few examine this at the nucleotide level. Our finding of increased M associated with KRAS p.Gly12Val and p.Gly12Asp is partially consistent with these studies[30-35]. The KRAS p.Gly12Val mutation disrupts cell cycle/apoptosis gene regulation, reduces apoptosis, and promotes angiogenesis via interleukin-8 signaling[27]. It is also associated with increased tumor budding, C-X-C chemokine receptor type 4 expression, and AKT serine/threonine kinase activation, enhancing invasion and intravasation[36]. Furthermore, KRAS p.Gly12Val has been linked to decreased tumor-infiltrating lymphocytes and increased tumor-stromal content, suggesting immune evasion[37].
Our study confirms prior work linking the BRAF p.Val600Glu mutation to increased pN+ in CRC[38,39]. This mutation’s aggressiveness may be due to several mechanisms. It promotes metastasis via vasodilator-stimulated phosphoprotein phosphorylation and filopodia formation[40]. The mutation localizes BRAF to the plasma membrane, where it interacts with vasodilator-stimulated phosphoprotein and catalyzes Ser157 phosphorylation, essential for filopodia formation and thus, invasion and metastasis[40] Beyond MAPK pathway activation[39], BRAF p.Val600Glu mutation induces a DNA damage response that can impair p53, further increasing invasiveness and metastatic potential[41].
In our prior study of this CRC patients population, we identified KRAS mutations, specifically p.Gly12Cys, p.Gly12Val, and p.Gly13Asp, as being linked to increased risk of all-cause death in mCRC patients, including those receiving systemic therapy[42]. These findings highlight the clinical heterogeneity of KRAS mutations and caution against grouping mutations across different codons or exons in biomarker analyses or trial designs. Importantly, the presence of these specific alterations may warrant more intensive monitoring strategies. Conversely, the prognostic impact of the BRAF p.Val600Glu mutation appeared attenuated in treated patients, suggesting possible differences in therapeutic responsiveness[42]. Overall, these findings emphasize the value of specific KRAS and BRAF mutation profiling in enhancing prognostic precision and guiding personalized mCRC treatment strategies.
In key oncogenic proteins, such as KRAS and BRAF, amino acid substitutions can profoundly alter their structure and function, thereby contributing to cancer progression[5]. The KRAS p.Gly12Val mutation, though seemingly small (a subtle change, replaces the small glycine residue with the bulkier valine) introduces steric strain, favoring the active guanosine triphosphate-bound state and sustained MAPK/ERK pathway activation[16-19]. The KRAS p.Gly12Asp and p.Gly13Asp mutations, replacing glycine with negatively charged aspartic acid, drastically disrupt the electrostatic landscape, also leading to constitutive pathway activation[16-19]. Similarly, the BRAF p.Val600Glu mutation in the kinase domain disrupts polarity, causing aberrant MAPK activation and uncontrolled proliferation[20,21]. While these mutations are key drivers, tumorigenesis is complex and influenced by the microenvironment, stroma interactions, and epigenetic modifications[24].
These amino acid substitutions can impact protein stability and function, especially when there is a shift between polar and nonpolar residues. When polar residues are replaced with nonpolar ones, it can disrupt hydrogen bonds, destabilize the structure, and interfere with protein interactions[22]. On the other hand, switching nonpolar residues to polar ones can alter the hydrophobic core or surface, potentially leading to misfolding, aggregation, or changes in solubility[23]. The specific effect depends on the substitution’s location and functional significance within the protein[16].
This study has strengths, particularly its use of high-quality, real-world data that mirrors current clinical practice alongside reliable pyrosequencing to ensure solid internal validity. A large sample size also enhances the generalizability of the findings. Nucleotide-level analysis of KRAS, NRAS, and BRAF mutations offers a granular understanding of mutational processes. However, there are some limitations. Selection bias may be introduced into the study due to its retrospective design. Pyrosequencing specifically targets mutations at codons 12, 13, and 61 in KRAS and NRAS, as well as codon 600 in BRAF, potentially overlooking other clinically relevant mutations in these genes, and has 10% mutant allele sensitivity. While socioeconomic status was not directly measured, we adjusted for race/ethnicity, family history, and comorbidities, commonly used socioeconomic status proxies in cancer research, to mitigate potential screening biases. Although our multivariable regression models accounted for measured confounders, the impact of unobserved factors like residual confounding and other genetic alterations, cannot be excluded. As such, findings should be interpreted with caution.
CONCLUSION
This study provides preliminary evidence linking specific KRAS and BRAF hot-spot mutations to CRC tumor behavior and phenotype. KRAS p.Gly12Val and p.Gly13Asp mutations were linked to an increased likelihood of advanced tumor stage (pT4) compared to wildtype KRAS. Both KRAS p.Gly12Asp and p.Gly12Val mutations were linked to a higher likelihood of M, as opposed to the KRAS wildtype. The BRAF p.Val600Glu mutation showed a positive association with pN+. These findings highlight the differential impact of specific KRAS and BRAF mutations on CRC tumor phenotype and the need for more precise, genetically informed prognostic models, as TNM staging alone is limited by inherent intra-tumoral heterogeneity. Our study offers preliminary evidence to support these mutations’ prognostic and risk stratification potential beyond their established predictive value. However, validation through larger, multi-center prospective studies is needed to translate these findings into clinical practice. Until then, their clinical implications in CRC remain uncertain.
ACKNOWLEDGEMENTS
The authors would like to acknowledge Molecular Diagnostics Division staff at University of Texas Medical Branch who performed Pyrosequencing.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: United States
Peer-review report’s classification
Scientific Quality: Grade A, Grade B, Grade D
Novelty: Grade B, Grade C, Grade D
Creativity or Innovation: Grade B, Grade C, Grade D
Scientific Significance: Grade A, Grade C, Grade D
P-Reviewer: Chang YC, MD, United States; Lin WL, PhD, Assistant Professor, Taiwan S-Editor: Bai Y L-Editor: A P-Editor: Zhang YL
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