Clonal hematopoiesis in cancer

Clonal hematopoiesis (CH) is the expansion of somatically mutated hematopoietic stem cells. Clonal hematopoiesis of indeterminate potential (CHIP) occurs when CH is driven by mutations in myeloid driver genes in individuals without hematologic disorders. CHIP increases the risk of hematological malignancies and chronic inflammatory diseases. CHIP is also associated with a higher incidence of non-hematological malignancies, such as lung cancer. These associations underline the importance of CHIP in the development of both malignant and non-malignant diseases. Patients with cancer have higher prevalence of CHIP compared to the general population and are at risk of developing therapy-related myeloid neoplasms (t-MN). As the prognosis of t-MN patients is poor, identifying and managing cancer patients with CHIP at risk of developing t-MN is critical. Moreover, patients with solid tumors and CHIP have an excess mortality not fully explained by increased rates of hematologic or cardiovascular diseases. Thus, a knowledge gap remains in understanding the role of CHIP in cancer, both in solid tumor progression and as a precursor to high-risk t-MN. I propose to address key challenges in four interconnected areas of (1) early detection of CHIP, (2) systemic role of CHIP at the solid tumor-immune interface, (3) interception of CHIP evolution, and (4) precision diagnostics at progression to t-MN, using a multidisciplinary approach at the intersection of computational genomics, artificial intelligence, myeloid cell tumor biology, and precision oncology. I will develop tools for the early detection of CHIP during routine clinical care, elucidate the role of CH in tumor evolution, identify mediators of CHIP evolution towards t-MN, and define a novel molecular t-MN classification. This project has the potential to transform our understanding and management of CHIP in cancer.