KRAS Gene Mutations In Patients Research Articles

KRAS-mutated non-small cell lung cancer: new therapy strategies

Lung cancer remains one of the most dangerous and most common cancers, requiring constant improvement of diagnostic and treatment methods. The genetic heterogeneity of lung cancer forces us to search for new therapeutic targets in an attempt to achieve greater effectiveness for certain groups of patients. The purpose of the study was to update current knowledge about lung adenocarcinoma with a mutation in the KRAS gene, to consider new opportunities for personalized treatment of KRAS-mutated NSCLC and to form an image of a Russian patient who is potentially indicated for targeted therapy. Material and methods. A search of available literature sources published in the Pubmed, Cochrane Library, Elibrary database was carried out, publications covering the period from 2008 to 2023 were included. Results. The article discussed molecular genetic testing, including NGS next generation sequencing, and its role in determining the presence of KRAS gene mutations in patients with lung cancer. the effectiveness of targeted drugs, such as Sotorasib and Adagrasib was also discussed. The mechanism of action is aimed at suppressing the activity of the mutant KRAS G12C protein, which can significantly improve patient survival prognosis. We obtained data on the results of testing 935 patients with non-squamous non-small cell lung cancer from various medical centers in Russia. The KRAS gene mutation was identified in 160 (17.1 %) patients, of whom 96 (10.3 %) had KRAS G12C variant. The KRAS mutation was determined by PCR in 44 patients and by NGS (including on the FoundationOne platform) in 111 patients. Clinical characteristics, such as gender, age, smoking status, PD-L1 expression level, presence of co-mutations (TP53, STK11, KEAP1, were largely similar between patients from real-world clinical practice and patients included in the CodeBreak100 study. Conclusion. The research results confirm the high effectiveness of Sotorasib and Adagrasib for patients with the KRAS G12C mutation and open up new prospects in the treatment of lung cancer. The clinical data obtained from Russian patients demonstrate consistency with the patient profile from registration studies of these drugs. This once again demonstrates the need to expand the range of molecular genetic testing for timely identification of this group of patients and prescribing the most effective treatment for them.

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.

A multitask dual-stream attention network for the identification of KRAS mutation in colorectal cancer.

It is of great significance to accurately identify the KRAS gene mutation status for patients in tumor prognosis and personalized treatment. Although the computer-aided diagnosis system based on deep learning has gotten all-round development, its performance still cannot meet the current clinical application requirements due to the inherent limitations of small-scale medical image data set and inaccurate lesion feature extraction. Therefore, our aim is to propose a deep learning model based on T2 MRI of colorectal cancer (CRC) patients to identify whether KRAS gene is mutated. In this research, a multitask attentive model is proposed to identify KRAS gene mutations in patients, which is mainly composed of a segmentation subnetwork and an identification subnetwork. Specifically, at first, the features extracted by the encoder of segmentation model are used as guidance information to guide the two attention modules in the identification network for precise activation of the lesion area. Then the original image of the lesion and the segmentation result are concatenated for feature extraction. Finally, features extracted from the second step are combined with features activated by the attention modules to identify the gene mutation status. In this process, we introduce the interlayer loss function to encourage the similarity of the two subnetwork parameters and ensure that the key features are fully extracted to alleviate the overfitting problem caused by small data set to someextent. The proposed identification model is benchmarked primarily using 15-fold cross validation. Three hundred and eighty-two images from 36 clinical cases were used to test the model. For the identification of KRAS mutation status, the average accuracy is 89.95 1.23%, the average sensitivity is 89.29 1.79%, the average specificity is 90.53 2.45%, and the average area under the curve (AUC) is 95.73 0.52%. For segmentation of lesions, the average dice is 88.11 0.86%. We developed a novel deep learning-based model to identify the KRAS status in CRC. We demonstrated the excellent properties of the proposed identification through comparison with ground truth gene mutation status of 36 clinical cases. And all these results show that the novel method has great potential for clinicalapplication.

The study of rate and spectrum of frequency of mutations of gene KRAS in patients with colorectal cancer in the Republic of Kazakhstan

The sampling included tumor material of 332 patients diagnosed with colorectal cancer, fixed in formalin and enclosed in paraffin, and treated in oncology dispensaries and centers and in the Kazakh Research Institute of Oncology and Radiology in 2010-2014. After morphological evaluation of the material quality, the molecular genetic analysis was applied to establish mutation of the KRAS gene using polymerase chain reaction in real-time. The study established that KRAS mutation rate in patients with colorectal cancer had no reliable dependency with the region of their residence, since statistical analysis of pair "region of residence - all KRAS mutations" had value of correlation coefficient rp = 0.1 (p = 0.05). colorectal cancer It was established that there is no reliable dependence of rate of KRAS gene mutation in patients with colorectal cancer in the region of their residence. The high rate of occurrence of mutated type of gene was detected in 3 regions (Kyzyl-Orda, North Kazakhstan and Almaty) within the range of 58.3-76.5% of cases. The wild type of KRAS gene was most frequently detected in patients from the Karaganda region (65.5%), South Kazakhstan (71.4%) and Almaty (60.7%).

KRAS gene mutation in patients with primary colorectal cancer

Objective: KRAS mutation occurs in 30% to 50% of colorectal cancers. The aim of our study was to determine the frequency of KRAS mutations among patients with colorectal cancer; and the relationship with clinicopathologic features.
 Materials and Methods: 79 colorectal cancer cases at a hospital in Hai Phong of Vietnam were collected, including 45 colon cancer and 34 rectal cancer during January 2010 and July 2012. PCR amplification and DNA sequencing were used to detect mutations in exon 2 of KRAS gene. The study was based on informed consent and approval by the Ethics Committee of Viet Tiep Hospital.
 Results: KRAS mutation was found in 40.4% (225/557) colorectal cancer. All mutation locations were in codon 12. There was significant association (p < 0.05) between KRAS mutations, tumor size and tumor stage. No significant association was observed between KRAS mutations and gender, tumor location, tumor grade or histologic presence of mucin (p>0.05).
 Conclusion: Determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers
 Keywords: colorectal cancer, KRAS gene mutation, clinicopathology.

K-ras gene mutation as an early prognostic marker of colon cancer.

Due to increased colorectal cancer incidence there is a necessity of seeking new both prognostic and prediction factors that will allow to evolve new diagnostic tests. K-ras gene seems to be such a factor and its mutations are considered to be an early marker of progression of colorectal cancer. The aim of the study was to find a correlation between K-ras gene mutation in patients with diagnosed colorectal cancer and selected clinical parameters. A total of 104 patients (41 women and 63 men) with diagnosed colorectal cancer were included in this study. The average age of male group was 68.3 and in female group - 65.9. Samples were taken from paraffine blocks with tissue from diagnosed patients and K-ras gene mutation were identified. Afterwards the statistical analysis was made seeking the correlation between K-ras gene mutation incidence and clinical TNM staging system, tumour localisation, histological type, sex, age. K-ras gene mutations were detected in 20.1% of all colorectal cancers. Significantly higher rate of K-ras gene mutations were diagnosed among patients classified at stage I (40%), stage IIC (50%) and stage IV (50%) according to the TNM classification. The results of our study are compatible with other studies and indicate the correlation between K-ras gene mutation and colorectal cancer incidence. Identification of K-ras gene mutation may complement other diagnostic methods at early stage of colorectal cancer.

THE RELATIONSHIP BETWEEN K-RAS GENE MUTATION, SOME DEGREE OF DIFFERENTIATION AND TUMOR MARKERS IN ADVANCED COLORECTAL CANCER

K-ras gene mutation is common in non-hereditary colorectal cancer. Although the role as a predictive biomarker to anti-EGFR therapy is well defined, its role as a prognostic marker is uncertain. We studied the relationship between the incidence of k-ras gene mutation, the degree of differentiation and the status of tumor markers in patients with advanced colorectal cancer resistant to complex cancer treatment. METHOD: Multicenter, retrospective study done in three oncology clinics in Bucharest from 2010 to 2014. The study included 71 stage III and IV colorectal cancer patients, which underwent surgery and adjuvant polychemotherapy. Under treatment they had an unfavourable evolution, the disease evolved worst in the first year of treatment. We analysed the K-ras gene status, the degree of tumor differentiation and the CEA and CA19-9 tumor markers, in all these patients. RESULTS: Of the 71 studied patients, 27 (38%) had the K-ras mutation. From this, 20 (74.1%) had high levels of CEA, and 16 (59.3%) had significant increases of CA19-9. By comparison, the 44 patients (62%) who had the wild gene, had elevated CEA in 28 (63.6%) of the cases and in 23 (52.3%) of the cases the CA19-9 was elevated. The G1 degree of differentiation was present in 28 patients; 11 (39%) were k-ras(+) and 17 (6%) k- ras(–), G2 was present in 36 patients; 14(39%) k- ras(+) and 22 (61%) k- ras(–), and the G3 was present in 7 patients; 2 (29%) k- ras(+) and 5 (71%) k- ras(–). CONCLUSION: K-ras gene mutations in patients with advanced colorectal cancer are not associated with increased prognostic tumor markers values or with the degree of tumor differentiation. The incidence does not differ significantly from that of the patients without the mutation. Keywords: colorectal cancer, genetic mutation, K-ras, tumor markers.

Blinded Comparator Study of Immunohistochemical Analysis versus a 92-Gene Cancer Classifier in the Diagnosis of the Primary Site in Metastatic Tumors

Accurate tumor classification is fundamental to inform predictive biomarker testing and optimize therapy. Gene expression-based tests are proposed as diagnostic aids in cases with uncertain diagnoses. This study directly compared the diagnostic accuracy of IHC analysis versus molecular classification using a 92-gene RT-PCR assay for determination of the primary tumor site. This prospectively defined blinded study of diagnostically challenging cases included 131 high-grade, primarily metastatic tumors. Cases were reviewed and reference diagnoses established through clinical correlation. Blinded FFPE sections were evaluated by either IHC/morphology analysis or the 92-gene assay. The final analysis included 122 cases. The 92-gene assay demonstrated overall accuracy of 79% (95% CI, 71% to 85%) for tumor classification versus 69% (95% CI, 60% to 76%) for IHC/morphology analysis (P = 0.019). Mean IHC use was 7.9 stains per case (median, 8; range, 2 to 15). IHC/morphology analysis accuracy was 79%, 80%, and 46% when 1 to 6 (n = 42), 7 to 9 (n = 41), and >9 (n = 39) IHC stains were used, respectively, versus 81%, 85%, and 69%, respectively, with the 92-gene assay. Results from this blinded series of high-grade metastatic cases demonstrate superior accuracy with the 92-gene assay versus standard-of-care IHC analysis and strongly support the diagnostic utility of molecular classification in difficult-to-diagnose metastatic cancer.

EVALUATION OF DIAGNOSTIC SIGNIFICANCE OF MOLECULAR-GENETIC MARKERS IN РАNCREATIC ADENOCARCINOMA

The purpose of the study : to evaluate the diagnostic value of molecular genetic markers in pancreatic cancer. Subjects. Data on patients with pancreatic cancer and patients with chronic pseudo tumor-like pancreatitis. The point mutations in K-ras gene were analyzed using polymerase chain reaction (PCR); the mutations in BRCA1, 2 genes were determined, the status of methylation of promoter segment of р16INK4A gene was analyzed. 67 % patients with pancreatic cancer and 63,6 % patients with chronic pancreatitis detected the mutant K-ras gene. 6,7 % patients with pancreatic cancer revealed the BRCA1 gene mutations in the heterozygous state, 13 % patients revealed the gene BRCA2 mutations. Diagnosis of the K-ras gene mutations in patients with pseudo tumor-like pancreatitis is conjugated with high risk of transformation of the pancreas to adenocarcinoma. 41 % patients with pancreatic cancer detected aberrant hypermethylation of р16INK4A gene, which is indicative of its aggressive genotype and poor prognosis.

Diagnosis Value of Detection K-Ras Gene Mutations in Patients with Gastric Cancer

Mutations of K-ras gene have been proven to play important roles in human tumor progression. Point mutations of K-ras gene located in codons 61 are gene hot spot mutation regions in patients with gastric cancer. A simple and effective capillary electrophoresis (CE) method for point mutation detection in codon 61 of K-ras gene was established. The polymerase chain reaction (PCR) fragments included codon 61 of K-ras gene were analyzed by single-strand conformation polymorphism (SSCP)-CE method. The CE analysis was performed by using a 1×Tris–borate–EDTA (TBE) buffer containing 3.0% (w/v) poly (ethylene oxide) (PEO) (MW 300 000) under reverse polarity with 15 oC and voltage of 15 kV. Forty-two gastric cancer patients were analyzed using this developed method. K-ras gene mutation was found in 17 cases (40.5 %) and the results showed that K-ras gene mutation in gastric cancer tissue is a usual event, and the SSCP-CE was feasible for mutation detection of K-ras gene in populations. Detection of gene mutation of gastric cancer tissue by PCR - SSCP has a certain value to diagnosis of gastric cancer and to prevent gastric cancer associated with clinical and pathological features, living habits of different patients by detection mutation of K-ras gene codon 61.

Correlation between computed tomography findings and epidermal growth factor receptor and Kras gene mutations in patients with pulmonary adenocarcinoma

We examined the correlation between computed tomography (CT) findings and the incidence of epidermal growth factor receptor (EGFR) and KRAS mutations in lung adenocarcinoma. We analyzed the tumors of 136 patients with surgically resected primary lung adenocarcinoma. CT scans were evaluated for the presence of ground grass opacity (GGO), spiculation and the maximum diameter of the tumor was measured. SMart Amplification Process (ver. 2) was used to detect the presence of EGFR and KRAS mutations. EGFR and KRAS mutations were found in 56 (41.1%) and 25 (18.4%) of the 136 cases, respectively. Although no significant association was found between GGO and EGFR mutations (p=0.07), the EGFR mutation occurred more frequently in male patients with GGO than in those without GGO (p=0.04). The KRAS mutation occurred more frequently in patients whose tumor diameter was ≥ 31 mm than in those whose tumor diameter was <30 mm (p=0.003). Evaluation of CT findings may be helpful for determining the presence of EGFR and KRAS mutations, particularly when it is not possible to obtain a tumor specimen.

K-RAS gene mutations in patients with non-small cell lung cancer

背景与目的最近研究显示存在K-RAS基因突变的非小细胞肺癌患者难以从辅助化疗中获益，并且对表皮生长因子受体（epidermal growth factor receptor, EGFR）酪氨酸激酶抑制剂（tyrosine kinase Inhibitors, TKIs）耐药。这些发现提示K-RAS基因突变情况可作为EGFR TKIs疗效的预测指标。本研究中分析了中山大学肿瘤防治中心非小细胞肺癌患者肺癌组织中K-RAS基因突变情况。方法收集52例非小细胞肺癌患者的新鲜组织标本，采用PCR技术扩增K-RAS基因，然后进行DNA测序并进行相应分析。结果在52例患者中，2例患者肿瘤组织中的K-RAS基因的12号密码子存在突变（2/52, 3.8%）。统计学分析未发现K-RAS基因突变与性别、病理类型、吸烟情况以及肿瘤分化程度和分期间存在相互关系。结论非小细胞肺癌患者K-RAS基因突变率较低，与亚裔患者相近，而低于白种人患者。

Sensitive Detection of KRAS Mutations in Archived Formalin-Fixed Paraffin-Embedded Tissue Using Mutant-Enriched PCR and Reverse-Hybridization

Recently, evidence has emerged indicating that assessment of KRAS mutations before anti-epidermal growth factor receptor therapy improves outcome in patients with metastatic colorectal cancer (CRC). We report here a novel reverse-hybridization (RH) assay to screen for KRAS mutations in formalin-fixed paraffin-embedded colorectal tissue samples. We combined mutant-enriched PCR based on peptide nucleic acid clamping and RH of amplification products to nitrocellulose test strips that contained a parallel array of oligonucleotide probes targeting 10 frequent mutations in codons 12 and 13 of the KRAS gene. DNA mixing experiments, which included eight different tumor cell lines with known KRAS mutations, were performed to examine the sensitivity of mutation detection. All KRAS mutations present in tumor cell lines were unambiguously identified by the RH assay with 1% of each cell line DNA diluted in normal DNA. RH was then used to screen for KRAS mutations in 74 colorectal tumor and 4 normal control samples. Twenty-six (35%) of the 74 tumor samples showed KRAS mutations. No mutation was found in the four samples of normal colorectal tissue. DNA sequencing without previous mutant enrichment, however, failed to detect four (15%) out of 26 KRAS-positive formalin-fixed paraffin-embedded samples (FFPE). This finding suggests that even after microdissection, mutant sequences in a given DNA isolate can be rare and more sensitive methods are needed for mutation analysis.

Analysis of p53 and K-Ras Gene Mutations in Patients with Chronic Bronchitis Using Laser Capture Microdissection Microscope and Mutation Detection

Analysis of p53 and K-Ras Gene Mutations in Patients with Chronic Bronchitis Using Laser Capture Microdissection Microscope and Mutation Detection

Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.

The majority of lung carcinoma cases occur in current or former smokers. K-ras gene mutations are common in lung adenocarcinoma and have been associated with cigarette smoking, asbestos exposure, and female gender. In the current study, the authors examined the contribution of cigarette smoking to K-ras gene mutations in patients with primary lung adenocarcinoma. Smoking histories were obtained from 106 prospectively enrolled patients with primary adenocarcinoma of the lung. K-ras mutations were detected in the primary tumor using an allele-specific ligation assay. Ninety-two of the 106 patients (87%) with lung adenocarcinoma were smokers. Nonsmokers with this tumor were more likely to be women (11 of 14; 79%), whereas the majority of smokers (57%) were men. K-ras mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs. 0%; P = 0.001). The results of the current study confirm and extend previous observations that smokers with adenocarcinoma of the lung are more likely to have K-ras mutant tumors compared with nonsmokers. The strong link between cigarette smoking and K-ras mutations in adenocarcinoma of the lung supports the role of specific tobacco carcinogens in the etiology of this malignancy.

P53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer.

Cholangiocarcinoma occurs frequently in patients with primary sclerosing cholangitis (PSC). We evaluated the incidence and prognostic significance of p53 protein overexpression and K-ras gene mutations in patients with biliary tract cancer and PSC. p53 protein expression was determined in specimens from 12 patients with biliary tract cancer, using the antibody, D07. K-ras mutations were detected using DNA sequencing and a mutation ligation assay. Accumulation of p53 protein was detected in 6 of 12 tumors (50%). K-ras mutations were detected in 4 of 12 tumors (33%). Overall survival in patients with p53-negative tumors was significantly longer (P < 0.05) than that in patients with p53-positive (mutant) tumors. Similarly, overall survival was significantly longer (P < 0.05) in the absence of a K-ras mutation than in patients with a tumor containing a K-ras mutation. Mean interval from the time of diagnosis of PSC until the diagnosis of biliary tract cancer was significantly shorter (P < 0.05) in patients with p53 overexpression than in those patients without p53 overexpression (2 versus 47 months). p53 overexpression and K-ras mutations occur commonly in patients with PSC and biliary tract cancer and are associated with a shortened survival. Patients with longstanding PSC are less likely to have these genetic alterations and may have a better prognosis.

Prognostic value of K-ras mutations, ras oncoprotein, and c-erb B-2 oncoprotein expression in adenocarcinoma of the lung.

This trial was undertaken to determine the prognostic role of K-ras (p21), c-erb B-2 (p185) protein expression, and the presence or nonpresence of a K-ras gene mutation in patients with adenocarcinoma of the lung. This was a retrospective study of 103 patients with adeno- or large-cell carcinoma of the lung who had available paraffin-stored tumor material. The relation of several clinical variables to survival was analyzed. Immunohistochemical techniques were used to determine expression of p21 and p185. Polymerase chain reaction (PCR) and sequencing were used to determine K-ras mutation status. Tumor stage was the only nonmolecular clinical variable predictive of survival (p=0.0001). A combination of K-ras mutation and p 185 expression (p=0.0144), ras mutation and strong p21 expression (p=0.0137), and K-ras mutation and the combined expression of p21 and p185 were predictive of poor survival (p=0.0415) in univariate analysis of all patients. The sole presence of K-ras mutation was predictive of survival. Additionally, when combined with elevated p21 or p185 expression in a subset of patients with 4 or more years of follow-up, negative correlation with survival was observed.

Long-term follow-up of patients with chronic pancreatitis and K-ras gene mutation detected in pancreatic juice

BACKGROUND & AIMS: Conflicting reports have raised the question whether K-ras gene mutations in chronic pancreatitis are related to the development of pancreatic neoplasm. The aim of the present study was to clarify this issue by surveying patients with chronic pancreatitis and K-ras gene mutation over 4 years.METHODS: K-ras point mutations at codon 12 in duodenal juices obtained during exocrine function tests were examined by enriched polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequence analysis, and long- term follow-up of these patients was performed.RESULTS: K-ras gene mutation was found in 20 of 54 patients (37%) with chronic pancreatitis. The types of mutation were GAT in 7, GTT in 11, and TGT in 2 patients. Pancreatic neoplasm occurred in none of the mutation- positive patients over a mean follow-up period of 78 months.CONCLUSIONS: K-ras gene mutation in patients with chronic pencreatitis did not seem to be related to the development of pancreatic neoplasm during the follow-up period, and analysis of K-ras gene mutation seems of little use for diagnosing pancreatic neoplasm in patients with chronic pancreatitis.(Gastroenterology 1997 Aug;113(2):593-8)