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High-proportion LOY is likely an MDS associated aberration
Table 2. Loss of chromosome Y is associated with somatic mutations that are frequently present in myeloid neoplasia.
[%] LOY (total number of patients)
≥75% (32) 12 (9; 0.40)
10 (10; 0.36) 4 (4; 0.25) 4 (3; 0.48) 4 (3; 0.32) 3 (3; 0.37) 2 (2; 0.41) 2 (2; 0.27) 2 (2; 0.27) 2 (2; 0.31)
65 (25) 16 (50)
16 (50) 9 (28.1)
Number of somatic mutations (number of patients with mutations; mean VAF)
TET2 SF3B1 U2AF1 ZRSR2 ASXL1 JAK2 SETBP1 CBL SH2B3
STAG2
Total number of somatic mutations (number of patients with mutations) Number of patients with mutations in spliceosome components,
JAK2 and RUNX1 (%)
Number of patients with ≥2 mutations (%)
Number of patients with combinations of mutations in TET2, DNMT3A and/or ASXL1 (%)
5 (4; 0.36) 1 (1; 0.41) 0
0
1 (1; 0.07) 0
<25% (23)
2 (1; 0.33) 1 (1; 0.23) 0
0
1 (1; 0.43) 0
0
0 0 1 (1; 0.49)
0 0
13 (7) 2 (8.7)
2 (8.7) 1 (4.4)
00 00
25-49% (10)
50-74% (8)
0
0
0
0
1 (1; 0.05)
1 (1; 0.46) 00
7 (5) 1 (10)
1 (10) 1 (10)
9 (5) 1 (12.5)
3 (37.5) 2 (25)
Number of mutations and variant allele fraction in commonly mutated myeloid neoplasia-related genes.For details please see Online Supplementary Tables S2 and S3.[%] LOY: percentage of metaphases with loss ofY chromosome;VAF:variant allele fraction.
Discussion
LOY as a sole cytogenetic finding is one of the most
common somatic genomic alterations in blood and mar-
row of elderly men.5,34 LOY as a post-zygote genomic
alteration occurs at varying rates in different tissues,
including non-hematopoietic cells.5,35,36 Interest in LOY is
increasing because of the mounting evidence of a role of
LOY in various disorders including atherosclerosis, late-
stage age-related macular degeneration, Alzheimer dis-
ease, and autoimmune disorders such as primary biliary
cirrhosis and autoimmune thyroiditis.36-43 In addition,
mosaic LOY in blood has been associated with a higher
risk of all-cause mortality and overall shorter life
expectancy.39,43-45 LOY in blood is associated with an
increased incidence of concurrent diagnosis of non-
hematopoietic malignancies such as head and neck, col-
orectal, prostatic and pancreatic carcinomas and may
contribute to the increased incidence of some tumors in
males.39,46-53 LOY in neoplastic tissues has been reported
in various solid tumors, including carcinomas of urothe-
lium, pancreas, esophagus, head and neck, and kid- ney.46,49,54-57
LOY is also one of the most common recurrent cytoge- netic abnormalities seen in MDS. As MDS is predomi- nantly observed in older people, it is difficult to separate age-associated LOY from disease-associated LOY. Although marrow sampling has an inherent age bias since the incidence of myeloid neoplasms increases with age, marrow samples taken from young patients evaluat- ed for hematologic disorders do not demonstrate the same high incidence of LOY as that seen in the elderly.34 Consistent with published literature, in our cohort most patients were older than 65 years, with a median age of 75 years.
In an analysis conducted in 1992, in which convention- al karyotyping was used, the incidence of LOY was esti- mated at approximately 11% in patients with MDS and 4% in those with AML.8 Subsequently, in 1997, Garcia- Isidoro et al. demonstrated the presence of LOY in 29%
Table 3. Multivariate analysis demonstrates that percentage loss of chromosome Y is a statistically significant independent predictor of a diagnosis of myeloid neoplasia.
Characteristic
% LOY
≥75% LOY Age
Presence of
mutations
Number of genes mutated
Total number
of mutations
Odds ratio (95% CI)
1.026 (1.02-1.04) per 20% increase 8.83 (2.51-34.89) for entire range
6.17 (2.15-17.68)
0.99 (0.95-1.03) per 10 years 0.60 (0.04-7.87) for entire range
2 (0.78-5.15)
1.21 (0.86-1.71) per gene mutated 3.12 (0.40-24.53) for entire range
1.22 (0.90-1.65) per mutation
4.02 (0.48-33.35) for entire range
P-value (effective likelihood ratio test)
0.0005
0.0007 0.69
0.15
0.27
0.18
Multivariate analysis using a logistic regression model for prediction of a diagnosis of myeloid neoplasia with odds of diagnosis of myeloid neoplasia,95% confidence inter- val and P-value. 95% CI: 95% confidence interval; % LOY: percentage of metaphases with loss of Y chromosome).
of male patients diagnosed with MDS using fluorescence in situ hybridization studies on bone marrow.9
Some studies have suggested that the proportion of metaphases with LOY could be used to separate age- associated LOY from disease-associated LOY. In previ- ous analyses, the degree of LOY was not correlated with the severity of peripheral blood cytopenias.58,59 In an analysis published in 2000, Wiktor et al. identified that using 81% Y chromosome loss as a cut-off maximized the combined sensitivity (28%) and specificity (100%) for predicting the presence of disease states associated with LOY.2 In a subsequent study in 2011 by Wiktor and colleagues, restricted to men >50 years old,23 a myeloid neoplasm (MDS, MPN and AML) could be diagnosed in 64/161 patients with >75% metaphases with LOY.23 In another series, a cutoff of 21.5% LOY in CD34-positive blood cells was proposed to discriminate between age-
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