Pre-diagnostic clonal hematopoiesis of indeterminate potential among patients with a primary cancer and risk of second cancers.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an elevated risk of hematologic and solid cancers. We performed a prospective cohort study, including 63690 patients with a first diagnosis of primary cancer in the UK Biobank during 2006 to 2022, to investigate the association of pre-diagnostic CHIP with future risk of second cancers. Cox regression was employed to assess the association between pre-diagnostic CHIP and risk of developing second cancer among patients with primary cancer. We identified 2860 patients with and 60626 without pre-diagnostic CHIP. During a median follow-up of 3.9 years, patients with primary cancer with pre-diagnostic CHIP experienced a greater risk of any second cancer (hazard ratio 1.3, 95% confidence intervals 1.2-1.5), compared with those without pre-diagnostic CHIP. Increased risk of any second cancer was mainly noted for patients with pre-diagnostic CHIP and primary myelodysplastic neoplasia, myeloproliferative neoplasms, non-Hodgkin lymphoma, or breast cancer. Regarding types of outcome (i.e., second cancer), the excess risk was particularly high for second myeloid malignancy and non-myeloid hematological malignancy. The risk for a second cancer was mainly observed in DNMT3A-, TET2-, SRSF2-, or JAK2-mutant CHIP. These findings suggest increased awareness of second cancer risk among patients with primary cancer and pre-diagnostic CHIP.