Clinical significance of somatic mutation in unexplained blood cytopenia

L Malcovati, A Gallì, E Travaglino, I Ambaglio, E Rizzo, E Molteni, C Elena, VV Ferretti, S Catricalà, E Bono, Gabriele Todisco, Antonio Bianchessi, E Rumi, S Zibellini, D Pietra, E Boveri, C Camaschella, D Toniolo, E Papaemmanuil, S OgawaM Cazzola

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Abstract

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 1 of these genes. Carrying a somatic mutation with a variant allele frequency ≥0.10, or carrying 2 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 comutation 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 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio 5 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. © 2017 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)3371-3378
Number of pages8
JournalBlood
Volume129
Issue number25
DOIs
Publication statusPublished - 2017

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Blood
Genes
Mutation
Neoplasms
Hazards
Granulocytes
DNA
Spliceosomes
Myelodysplastic Syndromes
Gene Frequency
Anemia
Learning

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Clinical significance of somatic mutation in unexplained blood cytopenia. / Malcovati, L; Gallì, A; Travaglino, E; Ambaglio, I; Rizzo, E; Molteni, E; Elena, C; Ferretti, VV; Catricalà, S; Bono, E; Todisco, Gabriele; Bianchessi, Antonio; Rumi, E; Zibellini, S; Pietra, D; Boveri, E; Camaschella, C; Toniolo, D; Papaemmanuil, E; Ogawa, S; Cazzola, M.

In: Blood, Vol. 129, No. 25, 2017, p. 3371-3378.

Research output: Contribution to journalArticle

Malcovati, L, Gallì, A, Travaglino, E, Ambaglio, I, Rizzo, E, Molteni, E, Elena, C, Ferretti, VV, Catricalà, S, Bono, E, Todisco, G, Bianchessi, A, Rumi, E, Zibellini, S, Pietra, D, Boveri, E, Camaschella, C, Toniolo, D, Papaemmanuil, E, Ogawa, S & Cazzola, M 2017, 'Clinical significance of somatic mutation in unexplained blood cytopenia', Blood, vol. 129, no. 25, pp. 3371-3378. https://doi.org/10.1182/blood-2017-01-763425
Malcovati, L ; Gallì, A ; Travaglino, E ; Ambaglio, I ; Rizzo, E ; Molteni, E ; Elena, C ; Ferretti, VV ; Catricalà, S ; Bono, E ; Todisco, Gabriele ; Bianchessi, Antonio ; Rumi, E ; Zibellini, S ; Pietra, D ; Boveri, E ; Camaschella, C ; Toniolo, D ; Papaemmanuil, E ; Ogawa, S ; Cazzola, M. / Clinical significance of somatic mutation in unexplained blood cytopenia. In: Blood. 2017 ; Vol. 129, No. 25. pp. 3371-3378.
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abstract = "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 1 of these genes. Carrying a somatic mutation with a variant allele frequency ≥0.10, or carrying 2 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 comutation 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 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio 5 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. {\circledC} 2017 by The American Society of Hematology.",
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T1 - Clinical significance of somatic mutation in unexplained blood cytopenia

AU - Malcovati, L

AU - Gallì, A

AU - Travaglino, E

AU - Ambaglio, I

AU - Rizzo, E

AU - Molteni, E

AU - Elena, C

AU - Ferretti, VV

AU - Catricalà, S

AU - Bono, E

AU - Todisco, Gabriele

AU - Bianchessi, Antonio

AU - Rumi, E

AU - Zibellini, S

AU - Pietra, D

AU - Boveri, E

AU - Camaschella, C

AU - Toniolo, D

AU - Papaemmanuil, E

AU - Ogawa, S

AU - Cazzola, M

PY - 2017

Y1 - 2017

N2 - 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 1 of these genes. Carrying a somatic mutation with a variant allele frequency ≥0.10, or carrying 2 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 comutation 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 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio 5 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. © 2017 by The American Society of Hematology.

AB - 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 1 of these genes. Carrying a somatic mutation with a variant allele frequency ≥0.10, or carrying 2 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 comutation 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 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio 5 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. © 2017 by The American Society of Hematology.

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DO - 10.1182/blood-2017-01-763425

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JO - Blood

JF - Blood

SN - 0006-4971

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ER -