Pathological point of view on the atomic bomb-related solid cancers.

Eighty years have passed since the atomic bombings (A-bombing) of Hiroshima and Nagasaki in August 1945. Survivors represent an unparalleled and irreplaceable human cohort for comprehensively studying the long-term carcinogenic effects of radiation exposure. This review provides a pathological perspective on A-bomb radiation-related solid cancers. Key findings underscore the persistent nature of radiation-induced carcinogenesis: an increased risk of solid cancers has been evident for over 10 years post-bombing and continues to persist. Epidemiological data consistently demonstrate a linear dose-response relationship, with the risk of all solid cancers increasing by ∼40%-50% per Gy, notably without an apparent threshold. The phenomenon of multiple primary cancers is significantly affected by A-bomb radiation, suggesting a systemic predisposition. At a molecular level, evidence points to long-lasting genomic instability, characterized by constitutive activation of the DNA damage response in non-neoplastic epidermis of proximally exposed survivors. This persistent genomic disruption is a critical contributing factor to tumorigenesis. Furthermore, radiation-associated cancers exhibit distinct molecular features. For instance, specific gene fusions are prevalent in thyroid cancer, while HER2 and c-MYC co-amplifications are observed in breast cancer, and gene expression alterations are noted in gastric cancer, often differing from sporadic cases. Research into biomarkers, such as cdkn1a in a rat model of thyroid carcinogenesis, shows promise for identifying radiation effects from the early pre-cancerous phase. This comprehensive analysis highlights the profound and enduring impact of A-bomb radiation on human carcinogenesis. The insights derived from this unique cohort are profoundly relevant for understanding and mitigating global radiation health risks.