Genome analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki

Abstract

Ionizing radiation is a risk factor for myeloid neoplasms including myelodysplastic syndromes (MDS), and atomic bomb survivors have been shown to have a significantly higher risk of MDS. Our previous analyses demonstrated that MDS among these survivors had a significantly higher frequency of complex karyotypes and structural alterations of chromosomes 3, 8, and 11. However, there was no difference in the median survival time between MDS among survivors compared with those of de novo origin. This suggested that a different pathophysiology may underlie the causative genetic aberrations for those among survivors. In this study, we performed genome analyses of MDS among survivors and found that proximally exposed patients had significantly fewer mutations in genes such as TET2 along the DNA methylation pathways, and they had a significantly higher rate of 11q deletions. Among the genes located in the deleted portion of chromosome 11, alterations of ATM were significantly more frequent in proximally exposed group with mutations identified on the remaining allele in 2 out of 5 cases. TP53, which is frequently mutated in therapy-related myeloid neoplasms, was equally affected between proximally and distally exposed patients. These results suggested that the genetic aberration profiles in MDS among atomic bomb survivors differed from those in therapy-related and de novo origin. Considering the role of ATM in DNA damage response after radiation exposure, further studies are warranted to elucidate how 11q deletion and aberrations of ATM contribute to the pathogenesis of MDS after radiation exposure.

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: unbiased-whole exome sequencing.

Figure 2.

Pattern of nucleotide substitutions in the whole genomes of three patients in the proximally exposed group. The pattern of nucleotide substitution was examined in three patients in the proximally exposed group who were analyzed using whole genome sequencing. Frequencies of each pattern of substitution are represented on the y-axis.

Figure 3.

Somatic mutations in myelodysplastic syndromes (MDS) among A-bomb survivors. Each row and column represents a mutated gene and patient, respectively. Identified gene mutations are shown as blue (proximally exposed group) or yellow (distally exposed group) squares. Assumed functional pathways are shown on the far left. UPN: unique patient number; ENT: entered within a 2 km radius from the hypocenter within two weeks after the atomic bombing. RCUD: refractory cytopenia with unilineage dysplasia; RCMD: RC with multi-lineage dysplasia; RAEB: refractory anemia with excess blasts; ICUS: idiopathic cytopenia of undetermined significance; AML: acute myeloid leukemia. DE: distally exposed group; PE: proximally exposed group.

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.

Figure 5.

Frequencies of mutated genes categorized by assumed functional pathway. Frequencies were calculated as the percentage of patients in each group carrying mutated genes within the different functional pathways. ^*P=0.018 using Fisher’s exact test. DE: distally exposed group; PE: proximally exposed group.

Figure 6.

Copy number alterations in myelodysplastic syndromes (MDS) among A-bomb survivors. Each row represents the copy number alterations (CNA) in each patient. The order of patients was in accordance with the exposure distance. (A) CNA on whole chromosomes except for chromosome Y, (B) CNA on chromosome 11. DE: distally exposed group; PE: proximally exposed group.