Biological Aging Marker p16(INK4a) in T Cells and Breast Cancer Risk

SIMPLE SUMMARY: The association between cellular senescence, a hallmark of biological aging, and cancer risk has not been examined in population-based studies. To fill the gap, in this study, we assessed the relationship between p16(INK4a) mRNA expression in T cells, a marker of cellular senescence, with breast cancer risk and selected sociodemographic and lifestyle variables. Overall, we discovered that higher p16(INK4a) mRNA expression in T cells was associated with an increased risk of breast cancer. Also, we found that p16(INK4a) mRNA expression in T differed by age, race, family history of cancer, marital status, annual income, and smoking status. The results of this study provide evidence that cellular senescence plays a role in breast cancer development. Furthermore, our results also suggest that social demographics may modify cellular senescence and biological aging. ABSTRACT: Prior research has demonstrated that altered telomere length, a well-known marker for biological aging, is associated with various types of human cancer. However, whether such association extends to additional hallmarks of biological aging, including cellular senescence, has not been determined yet. In this two-stage study, we assessed the association between p16(INK4a) mRNA expression in T cells, a marker of cellular senescence, and breast cancer risk. The discovery stage included 352 breast cancer patients and 324 healthy controls. p16(INK4a) mRNA expression was significantly higher in individuals who were older, Black, and had family history of cancer than their counterparts in both cases and controls. p16(INK4a) mRNA expression also differed by marital status, annual income, and smoking status in cases. In the discovery stage, we found that increased p16(INK4a) mRNA expression was associated with 1.40-fold increased risk of breast cancer (OR = 1.40; 95%CI: 1.21, 1.68; p < 0.001). A marginally significant association was further observed in the validation stage with 47 cases and 48 controls using pre-diagnostic samples (OR = 1.28; 95%CI: 0.98, 2.97; p = 0.053). In addition, we found that p16(INK4a) mRNA expression was higher in tumors with selected aggressive characteristics (e.g., poorly differentiated and large tumors) than their counterparts. In summary, our results demonstrate that higher p16(INK4a) mRNA expression in T cells is a risk factor for breast cancer and further support the role of biological aging in the etiology of breast cancer development. Novelty and Impact Statements: The results from this study provide evidence that cellular senescence, a process of biological aging, plays a role in breast cancer etiology. In addition, our results also support that social demographics may modify cellular senescence and biological aging.