Mitchell Machiela

ScD

National Cancer Institute

Stadtman Investigator

PLCO (Learn more about this study)

2021-0014

Jun 14, 2021

Characterizing clonal expansion of large mosaic chromosomal alterations in leukocytes

Clonal mosaicism is the presence of two or more genetically different cell populations in an individual.(1) The clonal expansion of cells harboring post-zygotic (i.e., non-inherited) mutations results in these heterogeneous cellular populations, which have been associated with elevated cancer risk.(2–6) Clonal mosaicism in peripheral blood leukocytes, referred to as clonal hematopoiesis, has been robustly associated with increasing age, with approximately 30% of individuals having a detectable mosaic chromosomal alteration (mCA) by age 80.(7,8) A few initial studies of mosaicism have tracked clonal expansion of mosaic cellular populations and have observed that on average cellular fraction of mutated cells increases as age increases.(9–11) Clonal hematopoiesis is associated with increased risk of hematopoietic cancers, including lymphoid leukemia (OR= 28.94 [21.77, 38.50]), chronic lymphocytic leukemia (OR= 36.44 [26.75, 49.60]), and myeloid leukemia (OR= 3.88 [2.56, 5.90]),(12) suggesting that cellular factors related to the development and clonal expansion of mosaicism may be relevant forces in early carcinogenesis. Interestingly, not all individuals with mCAs progress on to develop a hematologic malignancy suggesting some mCAs are well tolerated. To improve understanding of the genetic and environmental drivers of clonal expansion, we propose a study to examine the clonal trajectories of PLCO individuals with detectable mCAs. We have identified individuals with mCAs in PLCO using existing genotyping data (GSA genotyping). Here we propose to extend this work by performing genotyping on serial samples that were collected from these individuals to examine changes over time.

References
1. Machiela MJ, Chanock SJ. Detectable clonal mosaicism in the human genome. Seminars in hematology. 2013.
2. Loh P-R, et al. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature. 2018.
3. Jacobs KB, et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet. 2012.
4. Zhou W, et al. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat Genet. 2016.
5. Xie M, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014.
6. Thompson DJ, et al. Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers. Nature. 2019.
7. Machiela MJ. Mosaicism, aging and cancer. Curr Opin Oncol. 2019.
8. Terao C, et al. The genomic landscape of clonal hematopoiesis in Japan. bioRxiv. 2019.
9. Bonnefond A, et al. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nature genetics. 2013.
10. Machiela MJ, et al. Characterization of large structural genetic mosaicism in human autosomes. AJHG. 2015.
11. Danielsson M, et al. Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals. EJHG. 2020.
12. Zekavat SM, et al. Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer. medRxiv. 2020.

Aim 1: Trace clonal trajectories for mosaic chromosomal alterations to identify endogenous and exogenous drivers associated with selection and clonal growth or reversion back to normal states. Our primary objectives are to characterize clonal expansion over time, identify relevant risk factors that promote expanded clonal hematopoiesis, and determine the effect sizes associated with these risk factors. This analysis will be performed using 1,572 subjects with previously detected mCAs from the PLCO atlas project within the intervention arm from the PLCO screening trial. Illumina GSA arrays will be used for genotyping and subsequent extraction of virtual karyotypes for detecting mCAs and measuring cellular fraction.

Aim 2: Examine the impact of measured relative telomere length on the trajectory and clonal expansion of mosaic chromosomal alterations. We will perform longitudinal qPCR telomere length assays to track the association between measured relative telomere length and the clonal expansion of mosaic chromosomal alterations. We will also investigate factors related to inherited components of telomere length by calculating a telomere length polygenic risk score from the genotyping data in Aim 1. This analysis will be performed in the same 1,572 sample subjects selected for Aim 1.

Aim 3: Investigate the relationship between epigenetic age acceleration and the occurrence and clonal expansion of mosaic chromosomal alterations. We will characterize how methylation-based measures of age acceleration (e.g., Horvath, Hannum, PhenoAge, GrimAge) as extracted from Illumina MethylationEPIC arrays are associated with the frequency of mCAs both overall as well as by chromosomal region, copy number state, cellular fraction affected, and number of detected events. We will further examine how baseline methylation measures of age acceleration promote clonal expansion of mCAs over time. This analysis will be performed using 250 subjects within the intervention arm from the PLCO screening trial with known high cell fraction mCA status from Aim 1 and 250 mCA-free controls.