Distinct and convergent effects of <i>SF3B1</i> mutations in human breast cancer.

Abstract

Tumor genomic profiling has uncovered many cancer drivers whose implications in terms of tumor biology and therapeutic actionability remain understudied. Hotspot mutations in <i>SF3B1</i> induce widespread transcriptomic alterations and occur across multiple cancer types. Despite this, the biological and clinical consequences of <i>SF3B1</i> mutations remain elusive. Characterization of the largest <i>SF3B1</i> mutant breast cancer clinical cohort to date identifies <i>SF3B1</i> driver mutations in approximately 2.5% of HR+ HER2- breast cancer, with strong enrichment of K700E substitutions, substantial variation in variant allele fraction (VAF), and significantly improved overall survival due to enrichment in Luminal A disease. In vitro and in vivo studies in representative cell models suggest several of the most prevalent <i>SF3B1</i> mutations have deleterious effects on cell growth, leading to selective loss of the mutation over time, providing a rationale for the low frequency and low VAF of <i>SF3B1</i> mutations in breast cancer. Though all introduced hotspot mutations limit growth and are reverted to wildtype (WT) over time, mutations at position R625 have a more pronounced phenotype than K700E, providing an explanation for the clinically observed skew in mutation frequencies. RNA and DNA sequencing analyses were used to identify characteristic pathway-level transcriptomic changes in <i>SF3B1</i>-mutant cells and identify copy number alterations as a mechanism of both improved mutation tolerability and a means to eliminate the mutation over time. These data suggest that while <i>SF3B1</i> mutations are enriched in some clinical contexts, their role in breast tumorigenesis is highly complex and dependent on secondary events that overcome their deleterious effects on cell growth and survival.