Rasopathy is mainly composed of the cardiofaciocutaneous syndrome, Costello’s syndrome, Noonan’s syndrome, and the multiple lentigines syndrome. In addition, Legius syndrome is also well-known due to loss-of-functional mutant SPRED1, negatively regulating Ras signal activation. There are major two questions; Firstly, the genotype-phenotype correlation remains to be unknown. While gain-of-functional oncogenic KRAS causes pancreatic adenocarcinoma, oncogenic mutant BRAF develops malignant melanoma and hairy cell leukemia. However, genetic syndromes associated with RAS mutations are rarely associated with the malignant neoplasms probably because of oncogene-induced senescence and the different functions of proto-oncogenes specific to the embryonic tissue development. Secondly, the susceptibility to constitutively-activated Ras/MAPK signal seems to be different depending on each organs or tissues. For instance, the common dermatological symptoms among LEOPARD, Noonan, and Legius syndrome are the dermal pigmentation and multiple nevi, which suggest that neural crest-derived melanocytes tend to be highly influenced by constitutively-activated Ras/MAPK signaling pathway and exhibit clonal expansion.
Good question. I believe that you have partly answered the question. It is conceivable that RAS mutation-induced signaling pathways use a set of signaling pathways that are negatively regulated by multiple layers of growth/tumor suppressors leading to the inhibition of neoplastic transformation to various extents in cell-type and tissue-dependent manner. However, other additional mechanisms are also likely.
A valid question, and I agree with Divaker, and as an additional argument I would also like to add this quote:
"Although many of the activating mutations are similar to activating somatic mutations seen in cancer, on the whole, they tend to be not as strongly activating. For example, the most common oncogenic BRAF mutation, V600E, does not occur in CFC syndrome and the specific KRAS mutations associated with NS are not the same as the known somatic mutations associated with cancer. It is likely that the strongly activating oncogenic mutations cannot be tolerated as germline mutations." (source: DOI: 10.1016/j.gde.2009.04.001)
Although rasopathies are also a result of constitutive activation of the MAPK pathway, the mutations found in cancers are more activating then those in rasopathies.
I imagine also that some affected individuals with rasopathies may have some unique adaptations or genetic differences that allow them to survive oncogenes while others die in utero. We should genotype these patients to see if there is an oncogenic RAS resistance mutation we could use to evaluate risk of healthy individuals to develop cancer. These gene signatures could also be present in parents of affected individuals and smokers/former smokers who do not develop cancer.
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