Clinical significance of somatic mutation in unexplained blood cytopenia

Abstract

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 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. (Blood. 2017;129(25):3371-3378)

Molecular Testing in Myelodysplastic Syndromes for the Practicing Oncologist: Will the Progress Fulfill the Promise?

“…A recent study evaluated 308 patients with MDS, MDS/myeloproliferative neoplasm overlap, or AML evolving from MDS [8]. Unsupervised statistical analyses showed that MDS associated with SF3B1 mutation (20.8%) is a distinct entity irrespective of current morphologic classification criteria [8] (Table 3).…”

“…A recent study evaluated 308 patients with MDS, MDS/myeloproliferative neoplasm overlap, or AML evolving from MDS [8]. Unsupervised statistical analyses showed that MDS associated with SF3B1 mutation (20.8%) is a distinct entity irrespective of current morphologic classification criteria [8] (Table 3). Additionally, patients with concurrent mutations of TET2 and SRSF2 or ZRSR2 showed significantly higher hemoglobin levels (12.1 vs. 9.6 g/dL; p 5 .003) and higher monocyte counts (2.95 vs. 2.05 3 10 9 /L; p 5 .017) compared with those without comutations [8].This study highlights the importance of somatic gene mutations in the morphological classification of MDS and sets the stage for molecular abnormalities being incorporated into disease definitions.…”

“…After the completion of the human genome sequencing project in 2001, several studies that used high-throughput sequencing technologies have identified recurrent somatic mutations that are important in MDS pathophysiology and contribute to its eclectic phenotype [5][6][7][8][9]. This genomic information also plays a role in establishing the diagnosis and prognostication [5][6][7] and may lead to more effective therapies for MDS.…”

Systematic STAT3 sequencing in patients with unexplained cytopenias identifies unsuspected large granular lymphocytic leukemia

“…5 Therefore, identification of STAT3 mutations and a subsequent diagnosis of LGL leukemia does not exclude the possibility of a concomitant MDS. However, recent findings suggest a high negative predictive value for underlying myeloid neoplasms in patients who have neither karyotypic abnormalities nor mutations in typical driver genes, 15 as was observed in these 4 patients. Therefore, we re-reviewed the bone marrow biopsy specimens for these 4 patients and found that none met the diagnostic criteria for an MDS.…”

“…[10][11][12][13][14][15] Despite the reported histories of MDSs, no MDS-associated mutations were identified. In contrast, each sample demonstrated an isolated somatic STAT3 SH2 domain mutation (Table 1).…”