Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations

• Published in: Blood Vol. 135; no. 13; pp. 1032 - 1043
• Main Authors: Pangallo, Joseph, Kiladjian, Jean-Jacques, Cassinat, Bruno, Renneville, Aline, Taylor, Justin, Polaski, Jacob T., North, Khrystyna, Abdel-Wahab, Omar, Bradley, Robert K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2020; American Society of Hematology
• Subjects: Cell Line, Tumor; Computational Biology - methods; Exons; Gene Expression Profiling; Genetic Association Studies; Humans; Life Sciences; Mutation; Myeloid Neoplasia; Penetrance; Phenotype; RNA Splice Sites; RNA Splicing; RNA Splicing Factors - genetics; Spliceosomes - genetics; Transcriptome
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2019002894

Genes encoding the RNA splicing factors SF3B1, SRSF2, and U2AF1 are subject to frequent missense mutations in clonal hematopoiesis and diverse neoplastic diseases. Most “spliceosomal” mutations affect specific hotspot residues, resulting in splicing changes that promote disease pathophysiology. However, a subset of patients carries spliceosomal mutations that affect non-hotspot residues, whose potential functional contributions to disease are unstudied. Here, we undertook a systematic characterization of diverse rare and private spliceosomal mutations to infer their likely disease relevance. We used isogenic cell lines and primary patient materials to discover that 11 of 14 studied rare and private mutations in SRSF2 and U2AF1 induced distinct splicing alterations, including partially or completely phenocopying the alterations in exon and splice site recognition induced by hotspot mutations or driving “dual” phenocopies that mimicked 2 co-occurring hotspot mutations. Our data suggest that many rare and private spliceosomal mutations contribute to disease pathogenesis and illustrate the utility of molecular assays to inform precision medicine by inferring the potential disease relevance of newly discovered mutations. •A subset of patients with hematologic malignancies carry rare spliceosomal gene mutations of unknown disease relevance.•Many rare and even private spliceosomal gene mutations create molecular phenocopies of hotspot mutations and are likely pathogenic. [Display omitted]