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High-proportion LOY is likely an MDS associated aberration
incidence of LOY with aging include the presence of shortened telomeres as well as late S-phase replication of the Y chromosome.38,62 Smoking appears to be the most common epidemiological association with mosaic LOY in the bone marrow.4,25,63
It is unclear how LOY contributes to the phenotypes associated with LOY. LOY may not be limited to myeloid lineages, as more frequent LOY has been report- ed in CD3-positive cells in the blood of elderly patients with MDS compared to those without MDS.14 While some investigators have suggested an immune regulato- ry component, deregulation of proteins encoded by the male-specific region of the Y chromosome region has been seen in neoplasms with LOY, raising the possibility of a direct function of these proteins in carcinogene- sis.48,64,65 In vitro models have demonstrated a tumor sup- pressor role of the Y chromosome in the context of pro- static carcinoma.66 Furthermore, identification of tumor suppressor roles of ZFY and UTY, which localize to the male-specific part of Y, suggests a more active role of LOY in oncogenesis.53 Both these genes have homo- logues on the X chromosome which escape X inactiva-
tion.53,67 However, constitutional 45, XO (Turner syn- drome) is not associated with an increased incidence of myeloid neoplasms.68
In conclusion, our findings demonstrate that a high pro- portion of metaphases with LOY (≥75% metaphases) in marrow is associated with a high frequency of molecular alterations in genes commonly mutated in myeloid neo- plasia and strongly associated with a contemporaneous or subsequent diagnosis of MDS. These observations sug- gest that high-proportion LOY is likely to be a true MDS- associated cytogenetic aberration rather than an inciden- tal finding due to aging.
Disclosures
No conflicts of interest to diclose.
Contributions
MO collected cases and compiled data. MO and OW reviewed cases. OW, RH and VN contributed cases. VN and SL analyzed NGS data. PC oversaw cytogenetic testing. DS provid- ed clinical information related to cases. All authors contributed to the preparation of the manuscript and the revision.
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