Insights into the clinical, platelet and genetic landscape of inherited thrombocytopenia with malignancy risk

Abstract

Inherited thrombocytopenia; Malignancy predisposition

Trombocitopenia hereditaria; Predisposición a malignidad

Trombocitopènia hereditària; Predisposició a malignitat

Inherited thrombocytopenia (IT) with germline variants in RUNX1, ETV6 or ANKRD26 carries a high risk (10%–45%) of developing haematological malignancy (IT-HM). We evaluated the clinical, platelet and molecular characteristics in 37 patients with RUNX1-related thrombocytopenia (RT), 9 with ETV6-RT and 20 with ANRKD26-RT. Genetic diagnosis was delayed by about 20 years from the identification of thrombocytopenia. Bleeding tendency was present in 25%–30% of RUNX1-RT and ANKRD26-RT patients. Platelet aggregation was impaired in 90% of all patients, while reduced activation and granule secretion were heterogeneous. Most RUNX1-RT patients had low glycoprotein Ia (GPIa) levels, which may be a useful disease biomarker. Sixteen distinct genetic variants in RUNX1, four in ETV6 and four in ANKRD26 were identified in patients. The clinical profile showed immune, skin, gastrointestinal and other comorbidities in many patients. One third of the cases developed a malignancy: This included eight RUNX1-RT patients with myelodysplastic syndrome (MDS), five with acute myeloid leukaemia (AML), and one with chronic myeloid leukaemia (CML) Ph+. One patient with ETV6-RT subsequently developed B-cell acute lymphoblastic leukaemia (B-ALL) during childhood. Three cases with ANKRD26-RT demonstrated a multifaceted clinical presentation, including B-ALL Ph+, MDS and breast cancer. The high incidence of HM development highlights the importance of early diagnosis in life.

This work was supported by grants from: Instituto de Salud Carlos III (ISCIII) & European Union (PI23/00624, PI24/01458); ISCIII & European Union- NextGeneration EU and for PRTR (PMP21/00052); CIBERER-ISCIII (CB15/00055); Fundación Séneca- Agencia de Ciencia y Tecnología de la Región de Murcia (21 920/PI/22); Gerencia Regional de Salud (GRS2551/A/22, GRS2907/A1/2023, GRS2727/A1/23); Sociedad Española de Trombosis y Hemostasia (SETH, Premio López Borrasca, Ayuda a Grupos de Trabajo & Beca Dr. Francisco España, 2024); and Real Fundación Victoria Eugenia (Premio Investigación 2023). AM-Q is funded by ‘Ayuda postdoctoral from Sociedad Española de Hematología y Hemoterapia (SEHH)’ and Ministerio de Ciencia, Innovación y Universidades-Programa Juan de la Cierva (JDC2023-052518-I). AS-F and AZ-C hold training grants from ISCIII (Rio Hortega CM23/00028, FI21/00157). LD-A holds a fellowship from Junta de Castilla y León (JCYL-EDU/1868/2022). The authors' research on Inherited Platelet Disorders is conducted in accordance with the objectives of the project ‘Functional and Molecular Characterization of Patients with Inherited Platelet Disorders’ of the Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC), supported by SETH.