The joint association of clonal hematopoiesis of indeterminate potential and biological aging with cancer risk among 332,911 individuals
Li Wang, Kaili Sun, Siqi Lu, Yuyang Zheng, Xueqing Jia, Yanjie Zhao, Lujia Shen, Jingyun Zhang, Jing Shao, Xiao Tan, Jie Sun, Zuyun LiuAbstract
Background
Clonal hematopoiesis of indeterminate potential (CHIP) and biological aging have been individually associated with increased cancer risks. However, their joint effect on cancer risks remains unknown.
Methods
We analyzed data from 332,911 participants at baseline in the UK Biobank. We defined CHIP as a pathogenic variant with variant allele fractions ≥2%. Biological aging was assessed by the phenotypic age acceleration (PhenoAgeAccel) and categorized as biologically younger and older. Associations of CHIP and biological aging with 25 cancers were assessed by Cox proportional hazard models. Interactions between CHIP and biological aging were tested on additive and multiplicative scales.
Results
CHIP was associated with higher risks of myeloid malignancies (HR 9.56, 95%CI 8.28-11.03), lung cancer (HR 1.61, 95%CI 1.42-1.82) and oesophageal cancer (HR 1.54, 95%CI 1.18-2.01). Biologically older participants had higher risks of hematologic neoplasms (HR 1.42, 95%CI 1.30-1.55) and various solid tumors compared with biologically younger participants. CHIP carriers who were biologically older had increased risks of hematologic neoplasms (HR 6.56, 95%CI 5.67-7.59) and various solid tumors compared with biologically younger participants without CHIP. The proportion of excess risk attributable to additive interaction was 40% for hematologic neoplasms and 27% for lung cancer. A significant multiplicative interaction was also observed for hematologic neoplasms (P interaction<0.001).
Conclusion
CHIP confers substantial cancer risk, amplified when participants are biologically older. Assessing CHIP and biological aging may serve as an effective strategy for early screening and risk stratification for hematologic neoplasms and lung cancer.