Clinical significance of somatic mutation in unexplained blood cytopenia

Luca Malcovati, Anna Gallì, Erica Travaglino, Ilaria Ambaglio, Ettore Rizzo, Elisabetta Molteni, Chiara Elena, Virginia Valeria Ferretti, Silvia Catricalà, Elisa Bono, Gabriele Todisco, Antonio Bianchessi, Elisa Rumi, Silvia Zibellini, Daniela Pietra, Emanuela Boveri, Clara Camaschella, Daniela Toniolo, Elli Papaemmanuil, Seishi Ogawa and Mario Cazzola

Key points

  • Mutation profiling has a high predictive value for identifying individuals with, or at high risk of developing a myeloid neoplasm

  • Patients with clonal cytopenia have a significantly higher risk of developing a myeloid neoplasm than those with no evidence of clonality


Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm. Using granulocyte DNA, we looked for somatic mutations in 40 genes that are recurrently mutated in myeloid malignancies. Overall, 435/683 patients carried a somatic mutation in at least one of these genes. Carrying one somatic mutation with a variant allele frequency equal to or greater than 0.10, or carrying two or more mutations had a positive predictive value for diagnosis of myeloid neoplasm equal to 0.86 and 0.88, respectively. Spliceosome gene mutations and co-mutation patterns involving TET2, DNMT3A, or ASXL1 had positive predictive values for myeloid neoplasm ranging from 0.86 to 1.0. Within subjects with inconclusive diagnostic findings, carrying one or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (HR=13.9, P<.001). The predictive values of mutation analysis were confirmed in the independent validation cohort. The findings of this study indicate that mutation analysis on peripheral blood granulocytes may significantly improve the current diagnostic approach to unexplained cytopenia, and more generally the diagnostic accuracy of myeloid neoplasms.

  • Submitted January 18, 2017.
  • Accepted April 14, 2017.