Concurrent Mutations in SF3B1 and PHF6 in Myeloid Neoplasms

SIMPLE SUMMARY: The advent of next-generation sequencing has elucidated the understanding of the genetic landscape of myeloid neoplasms. Most myeloid neoplasms carry more than one gene mutation at their initial presentation or develop them during the disease course. The patterns of and interactions between these mutated genes are of great research interest and may improve our ability to diagnose and prognosticate patients. It is known that certain gene mutations have a cooperative effect in the pathogenesis of myeloid neoplasms, whereas other gene mutations are mutually exclusive. A commonly cited example of mutually exclusive mutations is SF3B1 and PHF6. This observation, however, has never been rigorously assessed. Since SF3B1 and PHF6 mutations can both serve as drivers of mutations and play key roles in the development of myeloid neoplasms, it is of clinical importance to clarify this issue. We report the clinicopathologic and molecular features of 21 myeloid neoplasms with double SF3B1 and PHF6 mutations. We summarize that concurrent mutations in SF3B1 and PHF6 are rare, but they do exist in a variety of myeloid neoplasms. SF3B1 mutations usually occur as early initiating events whereas PHF6 mutations occur late, with a role in disease progression. The presence of a larger number of other co-mutated genes suggests that the neoplastic cells have gone through active clonal evolution. ABSTRACT: It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the patients. PHF6 mutations occurred either concurrently with SF3B1 mutations or in subsequent follow-up samples and are associated with disease progression and impending death in most cases. Most cases had co-mutations, the most common being ASXL1, RUNX1, TET2, and NRAS. With a median follow-up of 39 months (range, 3-155), 17 (81%) patients died, 3 were in complete remission, and 1 had persistent myelodysplastic syndrome. The median overall survival was 51 months. In summary, concurrent mutations in SF3B1 and PHF6 are rare, but they do exist in a variety of myeloid neoplasms, with roles as early initiating events and in disease progression, respectively.