Page 126 - 2020_02-Haematologica-web

M. Taguchi et al.
Table 1. Patients’ characteristics. Characteristics
Sex
Male
Female
MDS type (WHO, 2008) RCUD
RCMD RAEB-1 RAEB-2 MDS/AML ICUS
Age at diagnosis (y.o) Median
(range)
Exposure distance (km) Median
PE group (n=18)
9 9
2
7
3
4
1
1 2
P
0.31
0.79
0.85
<0 .001
0.86
0.31
DE group (n=17)
5 12
1 10 1 2 1
73 (57-86)
1.1
74 (53-83)
3.4*
(range)
Age at exposure (y.o)
Median
(range)
Number of chromosomal abnormality (G-banding)
0 (normal karyotype)
1-2 8 8
3 (complex) 6 2
(0.5-2.5)
12 (2-19)
4
(2.8-7.5)
12 (3-19)
7
*The data of three patients were excluded when calculating the exposure distance in the distally exposed (DE) group because they were not present at the time of the bombing but entered within a 2 km radius from the hypocenter within two weeks after the bombing.PE:proximally exposed;RCUD:refractory cytopenia with uni-lineage dysplasia;RCMD: RC with multi-lineage dysplasia; RAEB: refractory anemia with excess blasts; ICUS: idiopathic cytopenia of undermined significance; MDS: myelodysplastic syndromes; AML: acute myeloid leukemia.
stitution was cytosine-to-thymine (C to T) (Figure 2 and Online Supplementary Figure S3). Clonal heterogeneities of MDS in these patients were inferred from the analysis of variant allele frequencies of the identified somatic SNV (Online Supplementary Figure S4).
Comparison of mutated genes between the proximally exposed and distally exposed groups
Using the U-WES, B-WES-T, and T-S methods, somatic and oncogenic mutations were identified in 16 out of 18 patients (89%) in PE, and 12 out of 17 patients (71%) in DE groups (Figure 3 and Online Supplementary Tables S6, S8 and S9). Among these mutations, in DE group, TET2 was most frequently affected (5 out of 17 patients, 29%), fol- lowed by SF3B1 (3 out of 17, 18%) and STAG2 (18%) (Figure 4). However, none of the PE patients had TET2 or STAG2 mutations, and the most frequently mutated gene was SF3B1 (4 out of 18 patients, 22%). There was a statis- tically significant difference in the frequency of TET2 mutations between the two groups (P=0.019), but not for STAG2 (P=0.104). Mutations in TP53 were identified at very similar frequencies in the two groups: PE: 2 out of 18 patients (11%); DE: 2 out of 17 (12%) (P=1.00). There was also no significant difference in the frequency of RUNX1 mutations between the two groups (11% and 6% in PE and DE, respectively; P=1.00).
Mutated genes were categorized on the basis of their assumed roles in functional pathways (Figure 5 and Online Supplementary Table S10). We found that gene mutations
along the DNA methylation pathways were significantly less frequent in the PE group (1 out of 18 patients, 5.6%) than in the DE group (7 out of 17, 41%; P=0.018). Genes coding RNA splicing factors were mutated with equal fre- quency in both groups. Mutations in genes for transcrip- tion factors and the chromatin modification pathway were more frequent in PE than in DE without statistical significance (transcription factors, 39% and 24%, respec- tively, P=0.47; chromatin modification pathway, 33% and 12%, respectively, P=0.23).
Copy number alterations and affected genes on 11q
Copy number alterations were evaluated by SNP array or T-S as described in the Methods and the Online Supplementary Methods, although the T-S data did not cover whole chromosomes. Using these methods, we identified CNA in 11 out of 18 (61%), and 7 out of 17 patients (41%) in the PE and DE groups, respectively (Figure 6A and Online Supplementary Table S11). CNA in chromosomes 11 and 20 were more frequent in PE (Figure 6B and Online Supplementary Figure S5A). Among the CNA, 11q deletion was identified only in PE with statistically significant difference (33% and 0% in PE and DE, respec- tively; P=0.019). Copy number loss of chromosome 5q and chromosome 7 were identified with almost equal fre- quency in both groups [chromosome 5q: PE: 4 out of 18 patients (22%); DE: 2 out of 17 (12%), P=0.66; chromo- some 7: PE: 22%; DE: 5 out of 17 (29%), P=0.71] (Online Supplementary Figure S5B and C).
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