Project 1: Evaluation of radiation-associated clonal hematopoiesis among atomic-bomb survivors

Summary

Clonal hematopoiesis, which can develop during aging, is associated with increased risks of hematologic malignancy and cardiovascular disease. The long-term effects of radiation exposure on the development of clonal hematopoiesis have not been explored with next generation sequencing (NGS). This project hypothesizes that among atomic-bomb (A-bomb) survivors who were exposed to high-dose (>1 Gy) radiation several decades ago, clonal hematopoiesis is promoted with recurrent somatic mutations, particularly in epigenetic modifier genes, such as TET2 and DNMT3A, or DNA damage response genes, such as TP53 and PPM1D. In this study, clonal hematopoiesis with somatic mutations will be evaluated by performing NGS analysis using cryopreserved blood cells from A-bomb survivors. T-cell receptor (TCR) deep sequencing, which can determine T-cell clonal expansion not involving hematopoietic stem cells (HSCs), will also be conducted in the same samples to avoid inclusion of recurrent mutations originating from T cells in the NGS-based clonal hematopoiesis assessment. Moreover, we will assess plasma levels of three major alarmins—HMGB1, IL-33, and S100A9—in heavily (>1 Gy) and negligibly (<5 mGy) exposed survivors, in relation to radiation exposure and clonal hematopoiesis. Evidence from this NGS-based clonal hematopoiesis assessment may indicate the existence of a common molecular basis underlying elevated risks of cancer and non-cancer diseases in radiation-exposed individuals, i.e., somatic mutations relating to HSC expansion long after radiation exposure.