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Genome analysis for MDS among A-bomb survivors
Figure 1. Somatic mutations identified in coding exons of five patients in the proximally exposed group. Each numerical number on the bar charts represents the number of variants of each mutation type identified using whole exome sequencing. No splice site variants were identified among these five patients. U-WES: unbi- ased-whole exome sequencing.
There are several genes observed to be recurrently affected in MDS and acute myeloid leukemia on 11q, such as ATM, KMT2A, and CBL.3,11,16,17 Copy number loss of ATM, KMT2A, and CBL were identified in five, five, and four patients in the PE group, respectively (Table 2), while copy number gain of KTM2A and CBL were found in one patient in the DE group (Online Supplementary Figure S6). We also identified mutations in ATM on the remaining allele in two patients (U-WES-3 and -5) in the PE group; thus, both ATM alleles were affected in these patients. Alterations of ATM were significantly more frequent in PE than in DE patients (28% and 0%, respectively; P=0.046).
Discussion
To better understand how A-bomb radiation con- tributed to the pathogenesis of MDS among survivors, we analyzed DNA samples from these MDS patients using next generation sequencing and SNP arrays for the first time. We found no apparent increase in the number of SNV among MDS patients proximally exposed to A-bomb radiation compared with those reported for patients with de novo or secondary MDS/AML.5,11 The pattern of nucleotide substitutions was also similar to that observed in de novo cases with C-to-T substitution being the most frequent, although this analysis was performed for only three patients in our cohort. We previously reported that the number of chromosomal aberrations was significantly increased in MDS among A-bomb survivors, especially in proximally exposed patients.13 This finding led us to pre- dict increased nucleotide alterations in MDS among
patients in the PE group but this was not the case. In spite of the genotoxic effects of ionizing radiation, it did not apparently contribute to increase the mutational burden in MDS. This may be related to the specific nature of A- bomb radiation: one-off, whole-body exposure that was mostly external. This could explain, at least in part, the reason why there was no difference in survival of MDS patients between the PE and DE groups (Online Supplementary Figure S7), and between exposed and un- exposed de novo MDS, or by the distance from the hypocenter, as we previously reported.13,14 Considering that our previous study showed cytogenetic risk cate- gories (by revised-International Prognostic Scoring System) significantly divided survival for both MDS among survivors and those unexposed, the same cytoge- netic hits seemed to have had a similar influence on their survival.13,14
However, we found significant differences in the profile of mutated genes between proximally and distally exposed patients. TET2 mutations, which are one of the most frequent alterations in myeloid neoplasms including MDS,3,4 were not detected in the PE group but were observed in the DE group, as frequently as reported for de novo MDS (approx. 29%). This was related, at least in part, to the significantly less mutations along with DNA methylation pathways in the PE group, as TET2 is one of the major genes in this pathway. Mutations in TP53 and genes coding splicing factors, such as SF3B1, were compa- rable to those in de novo cases,3,4 and were equally frequent in the PE and DE groups. TP53 is the most frequently mutated gene in t-MN including t-MDS, and it is highly correlated with poor outcome.11 Our previous work
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