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Genome analysis for MDS among A-bomb survivors
12 patients with RAEB or AML, which was 34.3% (12 out of 35) of all participants.
Copy number alterations are frequently found in MDS.20,21 In this study, we found a significantly higher fre- quency of copy number loss for 11q in the PE group than in the DE group (P=0.019). Loss of chromosomes 5 or 7, which occurs more frequently in t-MDS (40-50%), and is usually accompanied by a complex karyotype, was observed at an almost equal frequency in the PE and DE groups but less frequently than in t-MDS. Although we did not analyze the entire genes within the commonly deleted region of 11q in the PE group, we detected mutations on the residual ATM allele in 2 out of 5 cases (U-WES-3 and U-WES-5) but not in KMT2A or CBL. The ATM mutations, p.D2448V and p.G2891D, were located in the FAT and PI3K domains, respectively. Because of the pathogenic nature of these mutations, U-WES-3 and U- WES-5 appeared to lack expression of functional ATM pro-
tein. Deletions or mutations of ATM have been reported in de novo MDS3,4,7,8,22 and it does not seem to be specific to MDS among A-bomb survivors. However, the significantly higher frequency of 11q deletion and the presence of bial- lelic alterations of ATM strongly suggested its importance in the pathogenesis of MDS among survivors.
Since ionizing radiation induces DNA double-strand breaks (DSB),23,24 deletions and translocations are frequent- ly observed as a consequence of exposure. Accordingly, our previous study demonstrated that chromosomal translocations were significantly increased in MDS among A-bomb survivors; however, the translocations involving 11q23 where KMT2A locates were rare.14 We observed a significantly higher frequency of 11q aberrations but not translocations among survivors, compared with MDS of unexposed patients.14 Taken together, these results indicat- ed that aberrations of 11q, especially hemizygous deletion of 11q, could be caused by A-bomb radiation.
Table 2. Copy number alterations and mutations of candidate genes in the frequently affected region on chromosome 11q.
Group
PE
UPN
U-WES-3 U-WES-4 U-WES-5 U-WES-7 U-WES-8 T-S-3
ATM
CNA Mutation
Loss D2448V Loss − Loss G2891D
Candidate genes KMT2A
CNA Mutation CNA
Loss − Loss Loss − Loss Loss − Loss Loss − −
CBL
Mutation
− − − − − − −
− −
Loss − − − − Loss − Loss − Loss
DE B-WES-11
Frequency of alterations
(CNAandmutations) 28%and0% 28%and6% 22%and6% in PE- and DE-group (P=0.046) (P=0.18) (P=0.34) Minus sign (−) indicates no copy number alterations (CNA) or mutations. PE: proximally exposed group; DE: distally exposed group.
−− Gain − Gain
Figure 4. Frequencies of somatic gene mutations in the proximally and distally exposed groups. Frequencies were calculated as the percentage of patients in each group carrying the different mutated genes.
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