Decoding Mosaic Chromosomal Alterations in Lymphoid Malignancy Risk and Outcomes - ABSTRACT Lymphoid malignancies are common forms of cancer and leading causes of death that currently have no approach for prevention nor interception. Early data support clonal hematopoiesis in the form of mosaic chromosomal alterations (mCAs) as a promising premalignant and prognostic biomarker. mCAs are somatic megabase-scale alterations that can be detected with high sensitivity from array-based genotyping of blood-derived DNA. Prior studies have found mCAs confer a 10-fold increased risk of developing a lymphoid malignancy and 2-fold increased risk of mortality. However, prior studies have not been powered to precisely investigate mCAs in major lymphoid subtypes. Deeper characterization by subtype is needed. The overall objective of this application is to determine the role of mCAs in risk and prognosis of lymphoid malignancies. Our central hypothesis is that mCA carriers have distinctive etiologies and inferior outcomes. The rationale for this project is that mCA events can be readily detected in peripheral blood and could allow for targeted screening and earlier detection of at-risk individuals, promoting future prevention. We will utilize our existing studies, the most diverse prospective cohorts of lymphoma survivors in the world, to evaluate mCAs across lymphoid malignancies. Aim 1 will evaluate the association between mCAs and risk of lymphoid malignancy subtypes. Our hypothesis is that certain mCA loci are associated with risk of specific lymphoid subtypes. We will first evaluate the effect of mCAs across subtypes in 34,519 prevalent cases compared to 63,103 controls. Then we will validate these results in 5,029 incident cases and >500,000 controls. Aim 2 will determine the prognostic role of mCAs in lymphoid malignancies. Our hypothesis is that patients with an mCA have worse outcomes than those without an mCA. We will examine outcomes in 10,353 patients from the MER and LEO cohorts, accounting for therapy, known prognostic factors, mCA loci, and ancestry. Aim 3 will elucidate the blood cell lineage of mCAs in patients with a lymphoid malignancy. We will compare mCA events from peripheral blood with chromosomal alterations in matched tumor tissue in 2,164 patients. Then we will generate data to explore if mCAs are restricted to lymphoid cells in lymphoid malignancy patients. Completing these aims will provide a deeper understanding of the relationship between mCAs and lymphoid malignancy subtypes. Together, these studies will pave the way for future modeling of lymphoid malignancy risk and prognosis. We anticipate that the results of this project will generate critical preliminary data for future research on mCAs, specifically regarding (a) mechanisms underlying the risk of lymphoid malignancies, (b) therapeutic and prognostic implications, and (c) broader outcomes, such as susceptibility to infections and cardiovascular disease. The resulting preliminary data and additional mentored training from this award will propel me towards my long-term goal of establishing an independent research program to improve prevention, interception, and outcomes of blood cancers.
