Integration of Germline and Somatic Variation Improves Chronic Lymphocytic Leukemia Risk Stratification

Both acquired mutations and germline genetic variation are and CHIP had the greatest discriminative ability, with predictive known risk factors for chronic lymphocytic leukemia (CLL). The utility waning 5 years after the measurement of CH. Sensitivity joint characterization of germline, acquired, and clinical risk has analyses removing individuals with abnormal blood cell counts the potential to improve CLL risk prediction. In this study, we and CH commonly observed in CLL showed persistent, increased investigated whether the inclusion of a CLL-associated polygenic discriminative ability. Evaluating cumulative absolute risk, the score (PGS) and two common types of clonal hematopoiesis CLL PGS and CH had improved ability to stratify CLL cases into (CH), autosomal mosaic chromosomal alterations (mCA) and higher-risk categories and controls into lower-risk categories. CH of indeterminate potential (CHIP), could improve CLL risk Overall, this analysis details the enhanced ability to identify in-stratification in 436,784 participants in the UK Biobank and a dividuals at high risk of CLL when integrating germline and replication set of 35,382 participants in the Prostate, Lung, Co- somatic data derived from peripheral blood. lorectal and Ovarian Cancer Screening Trial. Individual mCAs on chromosomes 11, 12, 23, 14, and 22, as well as CHIP mutations in Significance: Joint consideration of well-characterized clinical known lymphoid driver genes, were strongly associated with CLL characteristics with germline genetic variation and somatic mu-risk. Integrative models that included sex, age, smoking status, tations can enable chronic lymphocytic leukemia risk stratificablood cell traits, genetic similarity, CLL PGS, autosomal mCAs, tion to support clinical decision-making and early detection.