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Initial CDAS Request Approval
Aug 1, 2022
Characterization of serum immuno-oncology biomarker levels in PLCO participants with mosaic chromosomal alterations
Mosaic chromosomal alterations (mCAs) are the age-related clonal expansion of cells harboring large chromosomal alterations in individuals, which can be detected from genotyping of blood-derived DNA. These somatic alterations (i.e., non-inherited), can be in the form of loss of chromosome Y (LOY) in men, loss of chromosome X (LOX) in women, and autosomal mCAs. mCAs have been associated with elevated risk of both infection and cancer. mCAs are associated with overall incident infections (hazard ratio (HR)= 1.25 [1.15–1.36]), including sepsis (HR= 2.68 [ 2.25–3.19]), and pneumonia (HR= 1.76 [1.53–2.03]), with higher effect sizes noted in cancer patients. Further, mCAs are associated with infection severity, including incident sepsis mortality (HR= 2.04 [1.04–4.16]), pneumonia mortality (OR=1.40 [1.12–1.53]), and severe COVID outcomes (OR= 1.85 [1.15–2.99]). mCAs are also associated with an 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]), suggesting that cellular factors relevant for the development and clonal expansion of mCAs may be critical for improving understanding of the forces driving early carcinogenesis. Impaired immune response may be implicated in the underlying pathway; specifically, one genome-wide association study of expanded mCAs identified loci enriched at transcription regulation sites for immune cells. Additionally, mCAs have been hypothesized to alter the ability of immune cells to identify and clear pre-neoplastic cells or lesions. To improve understanding of the mechanisms underlying the relationship between mCAs, infection, and cancer, we propose a study to examine the association between 93 immuno-oncology biomarkers and mCAs in PLCO participants. The Olink immuno-oncology panel will be used to simultaneously analyze 92 proteins involved in processes such as immune response, chemotaxis, apoptosis, and metabolism. C-reactive protein (CRP), which is a reliable measure of inflammation, will also be measured using the Quantikine Human CRP Immunoassay. IL-6, TNF-α (markers on the Olink panel), and CRP have been associated with somatic point mutations, but these markers have not been evaluated in relation to mCAs. Many of the Olink biomarkers and CRP have been associated with cancer or cancer precursors. Specifically, pro-inflammatory biomarkers (such as IL-6, CRP and TNF-α) and chemokines have been associated with colorectal adenoma, lung cancer, non-Hodgkin lymphoma, and liver cancer. Due to the strong age-related associations for immune response, cancer, and mCAs, we propose integrated analyses to disentangle the interplay between immuno-oncology biomarkers and mCAs with measures of biological aging, including epigenetic age acceleration and telomere length.
1. Aim 1: Characterize the relationship between the occurrence and clonal expansion of mosaic chromosomal alterations and 93 immuno-oncology serum biomarkers. Our primary objective is to characterize how diverse immuno-oncology biomarkers, as measured using the Olink Immuno-Oncology panel and Quantikine Human CRP assay, are associated with the occurrence of mCAs. Our main aim is to examine differences in immuno-oncology biomarkers in individuals with mCAs and without mCAs. Further exploratory analyses will examine how serum biomarker levels differ across mCA characteristics such as chromosomal region, copy number state, and cellular fraction. We can follow up interesting biomarker associations using longitudinal mCA calls (associated with EEMS Study 2021-0014), to examine how baseline measures of these serum biomarkers are related to mCA clonal expansion over time. All analyses will adjust for known mCA drivers (e.g., sex, age, smoking status). Analyses for this aim will be performed using 100 subjects within the intervention arm from the PLCO screening trial with known high cell fraction mCA status and 100 mCA-free controls also from the intervention arm.
2. Aim 2: Investigate the relationship between immuno-oncology serum biomarkers and mosaic chromosomal alterations in the context of epigenetic age acceleration and telomere length. We will perform exploratory integrated analyses to stratify the relationship between immuno-oncology biomarkers and mCAs using methylation-based measures of age acceleration (e.g., Horvath, Hannum, PhenoAge, GrimAge) and qPCR measured telomere length. Integrated analyses which stratify by these two independent measures of biological aging (i.e., epigenetic age acceleration and telomere length) may uncover novel associations between mCAs and immuno-oncology biomarkers. This analysis will utilize data generated from EEMS 2021-0014 and will be performed in the same 200 sample participants selected for Aim 1.
Mitchell Machiela (National Cancer Institute)
Derek Brown (National Cancer Institute)
Aubrey Hubbard (National Cancer Institute)
Eric Engels (National Cancer Institute)
Jill Koshiol (National Cancer Institute)
Weiyin Zhou (National Cancer Institute)