Analysis of KRAS Mutation Status Prediction Model for Colorectal Cancer Based on Medical Imaging

This study retrospectively included some patients with colorectal cancer diagnosed by histopathology, to explore the feasibility of CT medical image texture analysis in predicting KRAS gene mutations in patients with colorectal cancer. Before any surgical procedure, all patients received an enhanced CT scan of the abdomen and pelvis, as well as genetic testing. To define patient groups, divide all patients into test and validation sets based on the order of patient enrollment. A radiologist took a look at the plain axial CT image of the tumor, as well as the portal vein CT image, at the corresponding level. The physician points the computer’s cursor to the relevant area in the image, and TexRAD software programs together texture parameters based on various spatial scale factors, also known as total mean, total variance, statistical entropy, overall total average, mean total, positive mean, skewness value, kurtosis value, and general skewness. Using the same method again two weeks later, the observer and another physician measured the image of each patient again to see if the method was consistent between observers. With regard to clinical information, the KRAS gene mutation group and the wild group of participants in the test set and validation set each had values for the texture parameter. In a study of patients with colorectal cancer, the results demonstrated that CT texture parameters were correlated with the presence of the KRAS gene mutation. The best CT prediction model includes the values of the medium texture image’s slope and the other CT fine texture image’s value of entropy, the medium texture image’s slope and kurtosis, and the medium texture image’s mean and the other CT fine texture image’s value of entropy. Regardless of the training set or the validation set, patients with and without KRAS gene mutations did not differ significantly in clinical characteristics. This method can be used to identify mutations in the KRAS gene in patients with colorectal cancer, making it practical to implement CT medical image texture analysis technology for that purpose.

Molecular and genetic features of colorectal carcinoma: pathomorphological demonstration of clinical cases and literature review

Background. Colorectal carcinoma (CRC) is one of the most widespread malignancies worldwide; its morbidity rate is on the third place amidst the most common cancers. According to present data, such molecular markers as CyD1, HIF1α, LC3B, p21, p53 as well as the detection of KRAS gene amplification could be used for evaluation of tumor grade, its invasiveness, risk of metastases, sensitivity to anti-EGFR treatment, and further prognosis for patient’s survive. Objective. The purpose of this study was to make a literature review of the CRC molecular diagnostic approaches and demonstrate 5 cases of colorectal carcinoma in patients of Dnipro-city region in purpose to reveal their molecular-genetic features. Methods. Five formalin fixed paraffin embedded specimens of colorectal carcinoma from patients of Dnipro-city region were evaluated pathomorphologically with histological, immunohistochemical and fluorescence in situ hybridization methods. Results. Case study revealed increased level of p53, p21, and LC3B expression, minor elevation of CyD1 and HIF1α expression in demonstrated samples. Amplification of KRAS gene was not found. Conclusion. Our data analysis had revealed multiple studies dedicated to CRC molecular diagnostics with controversial results, what could be explained by both variable methodological approaches and epidemiological peculiarities of CRC in different sites of the globe. Therefore, there is a necessity in empirical identification of the molecular-genetic features of colorectal carcinomas in patients of our region that could improve current state of the art in CRC diagnostic and treatment approaches. Achieved data are the result of the trial and our research of this issue is ongoing.

Targeting KRAS in NSCLC: Old Failures and New Options for “Non-G12c” Patients

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene mutations are among the most common driver alterations in non-small cell lung cancer (NSCLC). Despite their high frequency, valid treatment options are still lacking, mainly due to an intrinsic complexity of both the protein structure and the downstream pathway. The increasing knowledge about different mutation subtypes and co-mutations has paved the way to several promising therapeutic strategies. Despite the best results so far having been obtained in patients harbouring KRAS exon 2 p.G12C mutation, even the treatment landscape of non-p.G12C KRAS mutation positive patients is predicted to change soon. This review provides a comprehensive and critical overview of ongoing studies into NSCLC patients with KRAS mutations other than p.G12C and discusses future scenarios that will hopefully change the story of this disease.

Joint Effects of Co-Exposure to Polycyclic Aromatic Hydrocarbons Exposure and Smoking with XPC Polymorphisms on Damage in Exon 2 of KRAS Gene Among Young Coke-Oven Workers

Background Genetic polymorphisms may contribute to variable individual susceptibility to DNA damage induced by co-exposure to polycyclic aromatic hydrocarbons (PAHs) and smoking. Here, we evaluate the joint effects of co-exposure to PAHs and smoking with polymorphisms in XPC, alone or combined, on damage in exons. Methods 288 healthy male coke-oven workers were enrolled into this study, urinary 1-hydroxypyrene (1-OH-pyr), as an indirect and sensitive indicator of PAHs exposure, was detected. Base modification in exons of KRAS and BRAF gene, and polymorphisms of XPC were determined by real-time PCR in plasma samples. Results We observed urinary 1-OH-pyr was positively related to damage index of exon 2 of KRAS gene (KRAS-2) and damage index of exon 15 of BRAF gene (BRAF-15) (both p < 0.001), and KRAS-2 and BRAF-15 were both significantly associated with increased urinary 1-OH-pyr (both p trend < 0.001). A stratified analysis found that urinary 1-OH-pyr was found to be significantly associated with KRAS-2 in both smokers (p < 0.001) and nonsmokers (p < 0.05), while urinary 1-OH-pyr was significantly associated with BRAF-15 only in smokers (p < 0.001). Additionally, rs2228001 in the XPC gene was positively associated with KRAS-2 (p trend < 0.001), and the high levels of 1-OH-pyr were linearly associated with KRAS-2 only in rs2228001 GG+GT genotype carriers (p < 0.001); However, another SNP rs3731055 in the XPC gene was associated with lower KRAS-2 (p trend = 0.006), and the high levels of 1-OH-pyr were linearly associated with KRAS-2 only in rs3731055 GG genotype carriers (p < 0.001). Moreover, KRAS-2 significantly increased with high levels of 1-OH-pyr exposure, smoking, rs2228001 G-allele, and rs3731055 GG homozygote genotype, and we found the most severe KRAS-2 among subjects carrying all 4 of the above risk factors. Conclusions Our findings indicated that the co-exposure effect of PAHs and cigarette smoking could increase the risk of damage in exon 2 of KRAS by a mechanism partly involving XPC polymorphisms.

Age-dependent prognostic value of KRAS mutation in metastatic colorectal cancer

Background: The age-dependent prognostic impact of KRAS status in metastatic colorectal cancer (mCRC) is unknown. Materials & Methods: We used the National Cancer Database to evaluate the survival by KRAS status for age-groups <50, 50–69 and ≥70, adjusting for relevant patient and tumor characteristics. Results: mCRC patients (n = 26,095; 33.5%) had KRAS status reported, and 11,338 of these patients (43.4%) had mutations in the KRAS gene. Patients with KRAS mutations had worse overall survival than wild-type KRAS patients. In age-groups <50 years (23 vs 29 months; p < 0.001) and 50–69 (21 vs 23.4 months; p < 0.001), KRAS mutations were significantly associated with worse survival, whereas in the ≥70-year age-group, there was no significant association (14 vs 14 months; p = 0.34). Conclusion: We conclude that the age of patients influences the prognostic value of KRAS mutation in metastatic colorectal cancer.

Integrating Gene Mutation Mutual Exclusion Information Into Radiomics Algorithms to Improve Gene Mutation Prediction in Non-small Cell Lung Cancer

Purpose Gene mutations are mutually exclusive in non-small cell lung cancer (NSCLC). Using EGFR and KRAS as examples, this study aims to assess the significance of mutation mutual exclusion information in the optimization of radiomics algorithms for predicting gene mutation.Methods We retrospectively analyzed 161 NSCLC patients with 18F-FDG PET/CT scans and EGFR and KRAS gene mutation data. Patients were randomly divided into training and testing cohorts. The Pyradiomics toolkit was used for radiomics feature extraction. Based on these features, radiomics score (RS) models were developed for predicting KRAS mutations using the gradient boosting decision tree (GBDT) algorithm. Furthermore, to investigate the value of adding mutation mutual exclusion information, a composite model combining PET/CT RS and EGFR mutation status was developed using logistic regression. The area under the curve (AUC), specificity, sensitivity, and accuracy were calculated for model performance evaluation in the training and test cohorts. To test the generalizability of this optimization method, models for predicting EGFR mutation were established in parallel, with or without adding KRAS gene mutation information.Results Compared with CT, the PET/CT based RS model exhibited higher AUC (KRAS: 0.792 vs 0.426; EGFR: 0.786 vs 0.644). By integrating EGFR mutation information into the PET/CT RS model, the AUC, accuracy, and specificity for predicting KRAS mutations were all elevated in the test cohort (0.928, 0.857, 0.897 vs 0.792, 0.755, 0.769). Conversely, the composite model for predicting EGFR mutations could also be optimized by adding KRAS gene mutation information (AUC, accuracy, and specificity: 0.877, 0.776, 0.700 vs 0.786, 0.694, 0.567). By adding EGFR and KRAS exclusive mutation information, respectively, the composite model corrected 55.4% and 30.7% false positive cases produced by the PET/CT RS model in the test cohort, without sacrificing sensitivity.Conclusion Integrating the mutation status of a known gene is a potential method to optimize radiomics models for predicting another gene mutation. This method may help predict unconventional gene mutations when the second biopsy is clinically difficult to carry out.

Anticipating resistance to KRAS inhibition: a novel role for USP21 in macropinocytosis regulation

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Virtually all PDAC harbors an oncogenic mutation in the KRAS gene, making it the prime target for therapy. Most previous attempts to inhibit KRAS directly have been disappointing, but recent success in targeting some KRAS mutants presages a new era in PDAC therapy. Models of PDAC have predicted that identifying KRAS inhibitor resistance mechanisms will be critical. In this issue of Genes & Development, Hou and colleagues (pp. 1327–1332) identify one such mechanism in which the deubiquitinase USP21 up-regulates the nutrient-scavenging process of macropinocytosis, rescuing PDAC cells from Kras extinction.