International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 305-314 http://medscipublisher.com/index.php/ijmms 307 3.3 Impact on cellular processes KRAS mutations significantly impact various cellular processes, including proliferation, apoptosis, and metastasis. Oncogenic KRAS induces mitochondrial oxidative stress in pancreatic acinar cells, leading to increased generation of mitochondrial reactive oxygen species (mROS). This oxidative stress drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to pancreatic intraepithelial neoplasia (PanIN) through the upregulation of epidermal growth factor signaling (Liou et al., 2016). Additionally, KRAS mutations promote NIX-mediated mitophagy, which restricts glucose flux to the mitochondria and enhances redox capacity, thereby supporting glycolysis and disease progression (Humpton et al., 2019). The suppression of metastasis-related genes by KRAS also underscores its role in regulating cellular processes critical for tumor growth and dissemination (Muzumdar et al., 2017). Collectively, these mechanisms illustrate how KRAS mutations orchestrate a range of cellular activities to facilitate pancreatic cancer development and metastasis. 4 Detection and Analysis of KRASMutations 4.1 Techniques for detecting KRASmutations Detecting KRAS mutations in pancreatic cancer is crucial for diagnosis, prognosis, and treatment planning. Several advanced techniques have been developed to identify these mutations in various biological samples. Quantitative polymerase chain reaction (qPCR) is a reliable method for assessing KRAS mutations in tissue samples and fine-needle aspiration biopsies. Digital droplet PCR (ddPCR) is another highly sensitive technique that can detect KRAS mutations in biological samples, including serum and plasma (liquid biopsies) (Buscail et al., 2020). Additionally, chip-based digital PCR has shown promise in detecting KRAS mutations in circulating tumor DNA (ctDNA) from early-stage pancreatic cancer patients (Brychta et al., 2016). Multiplex digital PCR on a droplet array SlipChip is a novel method that allows for the precise quantification of multiple KRAS mutations, providing a robust tool for both research and clinical diagnostics (Hu et al., 2022). 4.2 Diagnostic significance and prognostic value The presence of KRAS mutations in pancreatic cancer has significant diagnostic and prognostic implications. Combining KRAS mutation assays with endoscopic ultrasound-guided cytopathology enhances the sensitivity, accuracy, and negative predictive value of cytopathology alone, improving the positive diagnosis of pancreatic cancer and its differentiation from benign conditions. KRAS mutations are detected in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are associated with a worse prognosis, both in advanced and resected tumors (Bournet et al., 2016; Ardalan et al., 2023). The concentration and fractional abundance of KRAS mutations in cfDNA are significant factors for progression-free survival and overall survival, making them valuable prognostic biomarkers (Kim et al., 2018). Interestingly, KRAS wild-type status, as detected by circulating tumor DNA analysis, may be associated with better clinical outcomes and could serve as a prognostic or predictive factor for treatment response (Teufel et al., 2015). 4.3 Case study: application of KRASmutation analysis in clinical settings A notable case study involves the application of KRAS mutation analysis in a clinical trial for patients with locally advanced pancreatic cancer (LAPC) treated with gefitinib and chemoradiation therapy. In this study, plasma KRAS mutations were monitored at multiple time points to assess disease progression and treatment response. The clearance or persistence of plasma KRAS mutations after treatment correlated with patient outcomes, demonstrating the potential of KRAS mutation analysis as a marker for survival and response to therapy (Chen et al., 2006). Another study evaluated the clinical applicability of multiplex detection of KRAS mutations in cfDNA from patients with PDAC. The findings indicated that higher concentrations of KRAS mutations in cfDNA were associated with poorer clinical outcomes (Figure 1; Figure 2), reinforcing the prognostic value of KRAS mutation analysis in managing pancreatic cancer (Kim et al., 2018). 5 Therapeutic Implications of KRASMutations 5.1 Current treatment strategies targeting KRASmutations KRAS mutations are a hallmark of pancreatic cancer, present in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases (Luo, 2021). Current treatment strategies have focused on targeting the KRAS signaling pathway
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