title: The molecular anatomy of the FIP1L1-PDGFRA fusion gene.
abstract: The FIP1L1-PDGFRA fusion gene is a recurrent molecular abnormality in patients with eosinophilia-associated myeloproliferative neoplasms. We characterized FIP1L1-PDGFRA junction sequences from 113 patients at the mRNA (n=113) and genomic DNA (n=85) levels. Transcript types could be assigned in 109 patients as type A (n=50, 46%) or B (n=47, 43%), which were created by cryptic acceptor splice sites in different introns of FIP1L1 (type A) or within PDGFRA exon 12 (type B). We also characterized a new transcript type C (n=12, 11%) in which both genomic breakpoints fell within coding sequences creating a hybrid exon without use of a cryptic acceptor splice site. The location of genomic breakpoints within PDGFRA and the availability of AG splice sites determine the transcript type and restrict the FIP1L1 exons used for the creation of the fusion. Stretches of overlapping sequences were identified at the genomic junction site, suggesting that the FIP1L1-PDGFRA fusion is created by illegitimate non-homologous end-joining. Statistical analyses provided evidence for clustering of breakpoints within FIP1L1 that may be related to DNA- or chromatin-related structural features. The variability in the anatomy of the FIP1L1-PDGFRA fusion has important implications for strategies to detect the fusion at diagnosis or for monitoring response to treatment.
authors.affiliation: III Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Walz
authors.forename: J
authors.initials: J
authors.lastname: Score
authors.forename: J
authors.initials: J
authors.lastname: Mix
authors.forename: D
authors.initials: D
authors.lastname: Cilloni
authors.forename: C
authors.initials: C
authors.lastname: Roche-Lestienne
authors.forename: R-F
authors.initials: RF
authors.lastname: Yeh
authors.forename: J L
authors.initials: JL
authors.lastname: Wiemels
authors.forename: E
authors.initials: E
authors.lastname: Ottaviani
authors.forename: P
authors.initials: P
authors.lastname: Erben
authors.forename: A
authors.initials: A
authors.lastname: Hochhaus
authors.forename: M
authors.initials: M
authors.lastname: Baccarani
authors.forename: D
authors.initials: D
authors.lastname: Grimwade
authors.forename: C
authors.initials: C
authors.lastname: Preudhomme
authors.forename: J
authors.initials: J
authors.lastname: Apperley
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
authors.forename: G
authors.initials: G
authors.lastname: Saglio
authors.forename: N C P
authors.initials: NC
authors.lastname: Cross
authors.forename: A
authors.initials: A
authors.lastname: Reiter
mesh_terms: D019457:Chromosome Breakage; D004802:Eosinophilia / Q000235:genetics; D005091:Exons; D015894:Genome, Human; D006801:Humans; D007438:Introns; D009196:Myeloproliferative Disorders / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D022821:RNA Splice Sites; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D011995:Recombination, Genetic; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion; D022821:RNA Splice Sites; D012333:RNA, Messenger; D039221:mRNA Cleavage and Polyadenylation Factors; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha