Aggressive systemic mastocytosis with the co-occurrence of PRKG2::PDGFRB, KAT6A::NCOA2, and RXRA::NOTCH1 fusion transcripts and a heterozygous RUNX1 frameshift mutation

M Poscente; D Tolomeo; A Arshadi; A Agostini; A L'Abbate; A G Solimando; O Palumbo; M Carella; P Palumbo; T González; J M Hernández-Rivas; L Bassi; R Isidori; M Dell'Aquila; G Trapè; R Latagliata; G Pessina; F Natoni; C T Storlazzi

doi:10.1016/j.cancergen.2024.03.002

Aggressive systemic mastocytosis with the co-occurrence of PRKG2::PDGFRB, KAT6A::NCOA2, and RXRA::NOTCH1 fusion transcripts and a heterozygous RUNX1 frameshift mutation

Cancer Genet. 2024 Mar 7:284-285:5-11. doi: 10.1016/j.cancergen.2024.03.002. Online ahead of print.

Authors

M Poscente¹, D Tolomeo², A Arshadi², A Agostini³, A L'Abbate⁴, A G Solimando⁵, O Palumbo⁶, M Carella⁶, P Palumbo⁶, T González⁷, J M Hernández-Rivas⁷, L Bassi¹, R Isidori¹, M Dell'Aquila⁸, G Trapè⁹, R Latagliata⁹, G Pessina¹, F Natoni¹, C T Storlazzi¹⁰

Affiliations

¹ UOSD Laboratorio di Genetica Medica, Ospedale Belcolle, Viterbo, Italy.
² Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy.
³ Department of Precision and Regenerative Medicine and Ionian Area, Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, Bari, Italy.
⁴ Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari (IBIOM), Consiglio Nazionale delle Ricerche, Bari, Italy.
⁵ Department of Precision and Regenerative Medicine and Ionian Area, Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, Bari, Italy; IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.
⁶ Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo Foggia, Italy.
⁷ Department of Medicine, Universidad de Salamanca, Department of Hematology, Hospital Universitario de Salamanca, IBSAL, IBMCC-Centro de Investigación del Cáncer (USAL-CSIC), Salamanca, Spain.
⁸ UOC Anatomia Patologica, Ospedale Belcolle, Viterbo, Italy.
⁹ UOC Ematologia, Ospedale Belcolle, Viterbo, Italy.
¹⁰ Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy. Electronic address: cleliatiziana.storlazzi@uniba.it.

PMID: 38471404
DOI: 10.1016/j.cancergen.2024.03.002

Abstract

Systemic mastocytosis (SM) is a myeloproliferative neoplasm displaying abnormal mast cell proliferation. It is subdivided into different forms, including aggressive systemic mastocytosis (ASM) and systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). Oncogenic genetic alterations include point mutations, mainly the KIT D816V, conferring poor prognosis and therapy resistance, and fusion genes, with those involving PDGFRA/PDGFRB as the most recurrent events. We here describe an ASM case negative to the KIT D816V and JAK2 V617F alterations but showing a RUNX1 frameshift heterozygous mutation and the co-occurrence of three fusion transcripts. The first one, PRKG2::PDGFRB, was generated by a balanced t(4;5)(q24;q32) translocation as the sole abnormality. Other two novel chimeras, KAT6A::NCOA2 and RXRA::NOTCH1, originated from cryptic intra-chromosomal abnormalities. The patient rapidly evolved towards SM-AHN, characterized by the persistence of the PRKG2::PDGFRB chimera, due to the presence of an extra copy of the der(5)t(4;5)(q24;q34) chromosome and an increase in the RUNX1 mutation allelic frequency. The results indicated that the transcriptional landscape and the mutational profile of SM deserve attention to predict the evolution and prognosis of this complex disease, whose classification criteria are still a matter of debate.

Keywords: ASM; Chimera; RUNX1 mutation; SM-AHN; translocation.