DefinitionThis section has been translated automatically.
proto-oncogene, which codes for so-called "small" G proteins. The RAS proteins are membrane-associated G proteins that play a central role in the regulation of growth and differentiation processes of cells. As GTP-binding proteins, Ras proteins regulate cellular processes that can be switched on or off "switch-like". The RAS gene is located on chromosomes 12p(KRAS), 11p(HRAS) and 1p13.2 (NRAS). It contains the blueprint for the homologous and structurally related p21 proteins K-RAS, N-RAS and H-RAS.
General informationThis section has been translated automatically.
Primarily, K(irsten)-RAS(KRAS) and H(arvey)-RAS(HRAS) were described by researchers Kirsten and Harvey as retroviral oncoproteins in rat sarcomas. Only later was the third oncogene of the RAS family, NRAS, (N(euroblastoma)-RAS) identified in neuroblastoma, as well as two alternative splice variants of KRAS: KRAS-4A and KRAS-4B.
The two splice variants as well as the 3 isoforms K/N/H-RAS differ in their approximately 25 amino acid long hypervariable region (HVR) at the C-terminal end of the protein, which is responsible for posttranslational modification.
The importance of the RAS gene for cell growth is highlighted by the evidence that mutations in the RAS gene are found in 20-30% of human tumors (see peripheral neurofibromatosis below).
KRAS mutants are clustered in lung (15.94%), colon (34.50%) and pancreatic (57.20%) cancers, whereas NRAS is predominantly found in skin (malignant melanoma) (15,53%) and nerve tumors (17.45%), HRAS in bladder (9.85%), cervix (8.21%) and salivary gland tumors (14.64%) as well as in tumors of the upper aerodigestive tract (8.04%).
Activating RAS mutations, are missense mutations in about 98% of cases. They lead to a change in the amino acid sequence with an accompanying conformational change in the switch region of the protein. This causes the RAS protein to lose its GTPase activity. This can no longer be stimulated even in the presence of GTPase activating proteins (GAP). The switch from the GTP-bound form to the GDP-RAS form is blocked. This leads to an accumulation of active RAS (GTP-bound Ras) and thus to a permanent growth-stimulating signal in the cell. Mutations in the RAS gene thus create a readiness of the cell for malignant transformation.
HRAS mutations are detected in 95% of cases in nevus sebaceus.
Clinical pictureThis section has been translated automatically.
In addition to the laboratory pathologies, microcirculatory disorders in the area of the fingers and toes (erythromelalgia) or the brain (visual or speech disorders, dizziness, migraine) are characteristic of ET. ET may progress to myelofibrosis (post-ET MF). The percentage is probably very low in so-called true (histologically confirmed) ET. In individual JAK2-positive patients, ET progresses to polycythaemia vera. The first sign is the slow increase in hematocrit during regular blood count checks. At the same time, some patients report the first occurrence of the aquagenic pruritus typical of PV.
The transition of ET into MDS/acute leukemia is rare. Since drug therapies such as hydroxyurea or busulfan may increase the risk of transition, they should be used with caution (Lengfelder E et al.2007).
The most common and most feared complication of ET is thrombosis in the venous and arterial systems . Arterial: mainly occlusion of the coronary arteries (myocardial infarction) and of the arteries supplying the brain (stroke).
Venous: venous thromboses of the lower extremities; also venous thromboses of the large vessels of the upper abdomen (portal, hepatic, splenic, mesenteric veins) and cerebral thromboses (e.g. sinus vein thrombosis. Concurrent hemorrhagic complications are possible (due to secondary von Willebrand factor deficiency).
ET and skin:
PVmay be associated with aquagenic pruritus.