Epstein-Barr virus.

All mammalian cells express three closely related Ras proteins: H-Ras, K-Ras and N-Ras that promote oncogenesis when mutationally activated at codons 12, 13 or 61. Despite a high degree of similarity between the isoforms, K-Ras mutations are far more frequently observed in cancer and each isoform displays preferential coupling to particular cancer types. We have examined the mutation spectra of Ras isoforms curated from large-scale tumour profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino acid substitution biases. These were unexpected given that these mutations occur in regions that share 100% amino acid sequence identity between the three isoforms. Importantly, many of the mutational biases were not due to differences in exposure to mutagens because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms together with isoform-specific differences in protein structure and signalling that may promote these distinct mutation patterns and differential coupling to specific cancers.

/pdf/a-comprehensive-survey-of-ras-mutations-in-cancer-54p06m1p9m.pdf

A comprehensive survey of Ras mutations in cancer

The p16INK4a/CDKN2A tumor suppressor and its relatives

Prevention of what

KRAS mutations are the most common genetic abnormalities in cancer, but the distribution of specifi cm utations across cancers and the differential responses of patients with specific KRAS mutations in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specifi cK RAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)–stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. Of note, KRAS G13D shows rapid nucleotide exchange kinetics compared with other mutants analyzed. This property can be explained by changes in the electrostatic charge distribution

/pdf/biochemical-and-structural-analysis-of-common-cancer-4nb8gi58g6.pdf

Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations

Loss of heterozygosity and microsatellite instability in human atherosclerotic plaques.

Detection of Epstein-Barr virus and human papillomavirus in nasopharyngeal carcinoma by the polymerase chain reaction technique

Evaluation of Parvo B19, CMV and HPV viruses in human aborted material using the polymerase chain reaction technique

Microsatellite instability in human atherosclerotic plaques.

The levels of expression and the incidence of codon 12 point mutations of the ras family genes were studied in 18 cases of leukemia, seven with acute myeloblastic leukemia (AML), three with acute lymphoblastic leukemia (ALL), four cases with chronic myelogenic leukemia (CML) and four cases with chronic lymphocytic leukemia (CLL). Elevated expression of the ras genes was found for 39%, 61% and 67% of the specimens for the H-ras, K-ras and N-ras, respectively. A trend was found between the overexpression of the N-ras gene and the acute leukemias: all 10 acute leukemias exhibited overexpression of the N-ras gene, while only two of the CML cases, both in blastic crisis, showed elevated levels of the N-ras gene. Codon 12 point mutations at the N-ras gene were found in two of seven cases (28%) with AML and one of four cases (25%) with CML. The only K-ras codon 12 point mutation was found in a patient with CLL. No mutations were found in the codon 12 of H-ras. Our data suggest that apart from the point mutations, overexpression of the ras family genes is important in the development of the disease.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.140725

M. Ergazaki

Papers

Loss of heterozygosity and microsatellite instability in human atherosclerotic plaques.

Detection of Epstein-Barr virus and human papillomavirus in nasopharyngeal carcinoma by the polymerase chain reaction technique

Evaluation of Parvo B19, CMV and HPV viruses in human aborted material using the polymerase chain reaction technique

Microsatellite instability in human atherosclerotic plaques.

Mutations and expression of the ras family genes in leukemias