Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts.

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Somatic mutations in RAS and related pathway genes such as NF1 have been strongly implicated in the development of cancer whilst also being implicated in a diverse group of developmental disorders named the "RASopathies"; including Neurofibromatosis 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), and capillary malformation-arteriovenous syndrome (CM-AVM). It remains unclear why i) there is little overlap in mutational subtype between Ras-driven malignancies associated with sporadic disease and those associated with the RASopathy syndromes, and ii) RASopathy-associated cancers are usually of different histological origin to those seen with sporadic mutations of the same genes. For instance, germline variants in KRAS and NRAS are rarely found at codons 12, 13 or 61, the most common sites for somatic mutations in sporadic cancers. An exception is Costello's syndrome, where germline variants in codons 12 and 13 of HRAS occur relatively frequently. Given recent renewed drug interest following early clinical success of RAS G12C and farnesyl transferase inhibitors, an improved understanding of this relationship could help guide targeted therapies for both sporadic and germline cancers associated with the Ras pathway.

Click here to read the full article @ Annals of oncology : official journal of the European Society for Medical Oncology


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