Clinical relevance of clonal hematopoiesis in persons aged ≥80 years
Marianna Rossi, Manja Meggendorfer, Matteo Zampini, Mauro Tettamanti, Emma Riva, Erica Travaglino, Matteo Bersanelli, Sara Mandelli, Alessia Antonella Galbussera, Ettore Mosca, Elena Saba, Chiara Chiereghin, Nicla Manes, Chiara Milanesi, Marta Ubezio, Lucio Morabito, Clelia Peano, Giulia Soldà, Rosanna Asselta, Stefano Duga, Carlo Selmi, Maria De Santis, Karolina Malik, Giulia Maggioni, Marilena Bicchieri, Alessia Campagna, Cristina Astrid Tentori, Antonio Russo, Efrem Civilini, Paola Allavena, Rocco Piazza, Giovanni Corrao, Claudia Sala, Alberto Termanini, Laura Giordano, Paolo Detoma, Aurelio Malabaila, Luca Sala, Stefano Rosso, Roberto Zanetti, Claudia Saitta, Elena Riva, Gianluigi Condorelli, Francesco Passamonti, Armando Santoro, Françesc Solé, Uwe Platzbecker, Pierre Fenaux, Niccolò Bolli, Gastone Castellani, Wolfgang Kern, George S. Vassiliou, Torsten Haferlach, Ugo Lucca, Matteo Giovanni Della Porta
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.