Ras protein abundance correlates with Ras isoform mutation patterns in cancer.

Activating mutations of Ras genes are often observed in cancer. The protein products of the three Ras genes are almost identical. However, for reasons that remain unclear, KRAS is far more frequently mutated than the other Ras isoforms in cancer and RASopathies. We have quantified HRAS, NRAS, KRAS4A and KRAS4B protein abundance across a large panel of cell lines and healthy tissues. We observe consistent patterns of KRAS>NRAS>>HRAS protein expression in cells that correlate with the rank order of Ras mutation frequencies in cancer. Our data provide support for the model of a sweet-spot of Ras dosage mediating isoform-specific contributions to cancer and development. However, they challenge the notion that rare codons mechanistically underpin the predominance of KRAS mutant cancers. Finally, direct measurement of mutant versus wildtype KRAS protein abundance revealed a frequent imbalance that may suggest additional non-gene duplication mechanisms for optimizing oncogenic Ras dosage.

Association of RAS mutations with early progression after first-line systemic therapy in patients with initially unresectable colorectal cancer liver metastasis

Purpose Patients with initially unresectable colorectal cancer with liver metastases (IU-CRLM) need to undergo first-line systemic therapy with the aid of chemotherapy. However, the driver gene attributed to early progression in IU-CRLM patients after first-line systemic therapy remains unclear. Our study explored the RAS mutation status related to early progression in IU-CRLM patients. Methods A total of 193 IU-CRLM patients with RAS status detection were retrospectively enrolled from December 2012 to January 2020. We defined early progression as tumour progression within 6 months after first-line systemic therapy. Univariate and multivariate logistic regression for early progression were implemented to identify the risk factors. Results RAS mutations were found in 51 (26.0%) IU-CRLM patients. A total of 107 (55.4%) patients were confirmed to have early progression after first-line systemic therapy. RAS mutation was significantly related to early disease progression (66.7% vs. 49.3%, P=0.033). Logistic analysis results showed that RAS mutation (OR=2.962, 95% CI 1.354-6.478, P=0.007) was an independent risk factor for early disease progression. Conclusions Mutated RAS was an important risk factor for early progression in IU-CRLM patients after first-line systemic therapy.

Mucinous Cystic Lesions of the Pancreas an EUS-FNA-based Study with ClinicoPathological Follow Up

Background: Mucinous cystic lesions of pancreas harbor a pre-malignant potential thus necessitating their distinction from the non-mucinous ones. To make this distinction, EUS-FNA cytology along with cyst fluid CEA and amylase levels are utilized in addition to endoscopic and radiological findings. Evaluation of K-ras mutations has emerged as a useful adjunct for the evaluation of mucinous cystic neoplasms of the pancreas. Aim: We aimed to study mucinous cystic lesions of the pancreas diagnosed on EUS-FNA cytology, in conjunction with cyst fluid CEA and amylase levels and the frequency of K-ras mutation in a cohort of patients seen at the largest cancer hospital in our country. Materials and Methods: After approval from the institutional review board, all the cases of mucinous cystic lesions of pancreas evaluated between July 2005 and August 2019 were reviewed. Patient data, including age, gender, endoscopic and radiological findings, cytological and/or histological diagnosis, cyst fluid CEA, and amylase levels were collected. Results: Twenty-three patients enrolled in the study demonstrated an equal gender distribution with a mean age of 67.4 years. The sensitivity of EUS-FNA for mucinous cystic lesions of the pancreas was 84.6%. Cyst fluid CEA levels were elevated in some MCNs but not IPMNs resulting in a sensitivity of 37.5%. The specificity of cyst fluid amylase was 90%. K-ras mutation was found to have a sensitivity and specificity of 50% and 100% respectively, for mucinous lesions of the pancreas. Conclusion: EUS-FNA is a useful technique for evaluation of pancreatic cystic lesions, especially since cytological diagnosis can be augmented by cyst fluid CEA and amylase levels. K-ras analysis can add further to the diagnostic utility of EUS-FNA

Infrequent RAS mutation is not associated with specific histological phenotype in gliomas

Background Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. Methods This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. Results RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. Conclusion RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.

The Role of K-Ras and P53 in Biliary Tract Carcinoma

Objective: Biliary tract cancers are among the most fatal subtypes of gastrointestinal cancer. The pathogenesis of these tumors involves several molecular alterations in the genes. This review article focuses mainly on the role of K-Ras (a proto-oncogene) and p53 (a tumor-suppressor gene) which are among the most commonly mutated genes, with K-Ras activation being detected in 50% to 75% and P53 inactivation in 30% to 40% of biliary tract carcinomas. Methods: PubMed and Google Scholar were searched using the terms TP53, KRAS, mutation, biliary tract carcinoma, cholangiocarcinoma, murine model. In total, 72 articles were reviewed of which 26 articles from the 21st Century were included in this review. The articles excluded were mere repetitions, duplicates or were irrelevant. No data was retrieved from posters, presentations, cell lines and symposiums. Moreover, experiments involving bile aspirations were not included in this review article. Results: Three studies conducted in China, Japan and Taiwan reported a positive correlation between K-Ras mutation and biliary tract carcinoma. Only one study conducted in China showed the sole correlation between p53 inactivation and biliary tract carcinoma. Among the studies conducted in China, Japan and Europe, only four showed a positive association between both K-Ras mutation and p53 inactivation and biliary tract carcinoma. Conclusion: K-Ras and p53 mutation both contribute to biliary tract carcinoma. K-Ras mutation, however, has a much higher frequency as compared to p53 inactivation in these cancers. Keywords: p53, K-Ras, mutation, biliary tract carcinoma, cholangiocarcinoma, murine models. Continuous..