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Myelodysplastic Syndromes
Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):555-564
Madhu M. Ouseph,1° Robert P. Hasserjian,2 Paola Dal Cin,1 Scott B. Lovitch,1 David P. Steensma,3 Valentina Nardi2 and Olga K. Weinberg1,4,∞
1Department of Pathology, Brigham and Women's Hospital; 2Department of Pathology, Massachusetts General Hospital; 3Department of Medical Oncology, Dana-Farber Cancer Institute and 4Department of Pathology, Boston Children’s Hospital, Boston, MA, USA
°Current address: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
∞Current address: UT Southwestern Medical Center, BioCenter, Dallas, TX, USA ABSTRACT
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 dif- ficult 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 pro- portion of metaphases with LOY is associated with the incidence of myeloid neoplasia-associated genomic alterations. To address this ques- tion, we identified bone marrow samples with LOY as an isolated cyto- genetic finding and used targeted next generation sequencing-based molecular analysis to identify common myeloid neoplasia-associated somatic mutations. Among 73 patients with a 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 a morphological diagnosis of myeloid neoplasm (P=0.004). Furthermore, ≥75% LOY was associated with a higher lifetime incidence of a diagnosis of myelodysplastic syn- dromes (MDS) (P<0.0001), and in multivariate analysis ≥75% LOY was a statistically significant independent predictor of myeloid neoplasia (odds ratio 6.17; 95% confidence interval: 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 bone marrow cells is associated with an increased likelihood of molecular aberrations in genes commonly seen to be altered in myeloid neoplasia and with morpholog- ical features of MDS. These observations suggest that ≥75% LOY in bone marrow should be considered an MDS-associated cytogenetic aberration.
Introduction
Loss of the Y chromosome (LOY) was first described in 1963 in cultured periph- eral blood leukocytes.1 LOY is one of the most common acquired somatic genomic alterations in men; present in approximately 6% of all male bone marrow kary- otypes and in 16% of karyotypes from abnormal marrows.2,3 The incidence of LOY in bone marrow cells increases proportionally with age, with up to 20% of healthy men over 80 years of age showing LOY by conventional marrow karyotyping.4,5
LOY is observed in association with myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), acute myeloid leukemias (AML) and B-cell
Correspondence:
OLGA K. WEINBERG
Olga.weinberg@UTSouthwestern.edu
Received: October 22, 2019. Accepted: March 19, 2020. Pre-published: March 19, 2020.
https://doi.org/10.3324/haematol.2019.240689
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