Decoding the mechanisms behind second primary cancers

Each year, millions of cancer survivors face a serious challenge: the development of second primary cancers (SPCs). SPCs refer to new malignancies that arise either after or simultaneously with a first primary cancer (FPC) in the same individual. With their high incidence and significant clinical impact, SPCs have become a leading cause of death among FPC survivors. A Chinese research team recently published a comprehensive review titled Decoding the mechanisms behind second primary cancers in the Journal of Translational Medicine, shedding new light on the mechanisms behind SPCs and offering valuable insights for future research and clinical approaches.

“The mechanisms underlying second primary cancers (SPCs) are extremely complex, involving multiple factors such as genetic alterations, tumor microenvironment, immune suppression, and hormonal regulation,” says Meiyuan Zeng, one of the study’s authors from Zhujiang Hospital of Southern Medical University. “This review systematically integrates the latest findings, providing a new understanding of the biological characteristics of SPCs and laying a solid foundation for future research.”

The research team found that the development of second primary cancers (SPCs) is primarily influenced by several key mechanisms: radiotherapy- or chemotherapy-induced DNA single-strand breaks and telomere damage lead to genomic instability, which in turn promotes carcinogenesis; phenotypic and metabolic changes in tumor-associated stromal cells facilitate malignant transformation; abnormal hormone levels, such as IGF-1 and estrogen, drive the initiation and progression of SPCs; immunosuppression may promote SPCs by allowing malignant cells to escape immune surveillance and reactivate dormant viruses; abnormal gene methylation and EGFR signaling abnormalities further accelerate tumor development; and proliferating cancer cell-released circulating cell-free DNA may transfect or transform normal cells, contributing to the onset of second primary cancers.

Professor Peng Luo, the principal investigator of the study from Zhujiang Hospital, Southern Medical University, further emphasized:“This review not only consolidates existing knowledge but also calls for a deeper exploration of SPC mechanisms, particularly the roles of intratumoral microbes, single-cell multi-omics, and metabolomics in understanding SPC mechanisms and screening. We hope these insights will inspire innovative approaches to enhance the early detection and precise prevention of SPCs.”