Activating mutations of N- or K-Ras oncogenes distinguish MM from MGUS. In one large study, activating mutations of Ras at codon 12, 13 or 61 were identified in approximately 40% of MM tumors at the time of diagnosis, and a limited analysis indicated mutations in 49% of tumors at the time of relapse; 60% of the mutations were in N-Ras and 40% in K-Ras. A second large study reports a slightly higher incidence of Ras mutations, with K-Ras affected more often than N-Ras. The frequency of activating Ras mutations is relatively independent of the plasma cell labeling index and stage of myeloma. The same mutations are found in 17/38 (45%) of HMCL. Strikingly, fewer than 5% of MGUS tumors have Ras mutations. Although H-RAS is expressed at high levels in some MM tumors, no activating mutations of H-Ras have been reported (possibly because most studies have focussed
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