Resequencing analysis of the candidate tyrosine kinase and RAS pathway gene families in multiple myeloma.

Multiple myeloma (MM) is an incurable, B-cell malignancy characterized by the clonal proliferation and accumulation of malignant plasma cells in bone marrow. Despite recent advances in the understanding of genomic aberrations, a comprehensive catalogue of clinically actionable mutations in MM is just beginning to emerge. The tyrosine kinase (TK) and RAS oncogenes, which encode important regulators of various signaling pathways, are among the most frequently altered gene families in cancer. To clarify the role of TK and RAS genes in the pathogenesis of MM, we performed a systematic, targeted screening of mutations on prioritized RAS and TK genes, in CD138-sorted bone marrow specimens from 42 untreated patients. We identified a total of 24 mutations in the KRAS, PIK3CA, INSR, LTK, and MERTK genes. In particular, seven novel mutations in addition to known KRAS mutations were observed. Prediction analysis tools PolyPhen and Sorting Intolerant from Tolerant (SIFT) were used to assess the functional significance of these novel mutations. Our analysis predicted that these mutations may have a deleterious effect, resulting in the functional alteration of proteins involved in the pathogenesis of myeloma. While further investigation is needed to determine the functional consequences of these proteins, mutational testing of the RAS and TK genes in larger myeloma cohorts might also be useful to establish the recurrent nature of these mutations.