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Ouseph, Madhu M; Hasserjian, Robert P; Dal Cin, Paola; Lovitch, Scott B; Steensma, David P; Nardi, Valentina; Weinberg, Olga K
Haematologica, 02/2021, Letnik: 106, Številka: 2Journal Article
Loss of the Y chromosome (LOY) is one of the most common somatic genomic alterations in hematopoietic cells in men. However, due to the high prevalence of LOY as the sole cytogenetic finding in the healthy older population, differentiating isolated LOY associated with clonal hematologic processes from aging-associated mosaicism can be difficult in the absence of definitive morphological features of disease. In the past, various investigators have proposed that a high percentage of metaphases with LOY is more likely to represent expansion of a clonal myeloid disease-associated population. It is unknown whether the proportion of metaphases with LOY is associated with the incidence of myeloid neoplasia-associated genomic alterations. To address this question, we identified marrow samples with LOY as isolated cytogenetic finding and used targeted next generation sequencing-based molecular analysis to identify common myeloid neoplasia-associated somatic mutations. Among 73 patients with median age of 75 years (range 29-90), the percentage of metaphases with LOY was <25% in 23 patients, 25-49% in 10, 50-74% in 8 and ≥75% in 32. A threshold of ≥75% LOY was significantly associated with morphologic diagnosis of myeloid neoplasm (p = 0.004). Further, ≥75% LOY was associated with a higher lifetime incidence of diagnosis of myelodysplastic syndromes (MDS; p < 0.0001), and in multivariate analysis ≥75% LOY was a statistically significant independent predictor of myeloid neoplasia OR 6.17; 95% CI = 2.15-17.68; p = 0.0007. Higher LOY percentage (≥75%) was associated with greater likelihood of having somatic mutations (p = 0.0009) and a higher number of these mutations (p = 0.0002). Our findings indicate that ≥75% LOY in marrow is associated with increased likelihood of molecular alterations in genes commonly seen in myeloid neoplasia and with morphologic features of MDS. These observations suggest that ≥75% LOY in bone marrow should be considered an MDS-associated cytogenetic aberration.
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