Characterizing cancer susceptibility mechanisms for TERT/CLPTM1L and other telomere-related regions

ABSTRACT Inherited genetic variation within a highly pleiotropic locus at 5p15.33 impacts risk for >15 cancer types, >10 blood cell traits, telomere length (TL), epigenetic aging, clonal hematopoiesis, pulmonary fibrosis, uterine fibroids, and other disease-related traits. This ~150 kb region contains the TERT (telomerase reverse transcriptase) gene, which encodes the catalytic subunit of the telomerase enzyme, responsible for maintaining TL in stem cells. Epidemiological research suggests that individuals with longer TL are at increased risk for multiple types of cancer, likely due to increased proliferative capacity and the accompanying burden of replication errors in cells with longer TL. The striking pleiotropy observed for the many causal variants at 5p15.33 points to etiological connections between cancer and aging-related changes in the proliferative potential of cells. However, no attempts have been made to systematically characterize and compare the many association signals across all 5p15.33-associated traits, and we know little about the biological mechanisms at this locus. This knowledge gap is due, in part, to the fact that TERT is primarily expressed in stem and progenitor cells, making the identification of regulatory variants challenging. To elucidate the biological mechanisms at 5p15.33 and characterize relationships among TL, cellular aging, and cancer risk, we will integrate and analyze (1) large-scale genetic association data across many phenotypes, (2) multi-omic QTLs in stem/differentiating cells and other contexts and (3) somatic events across multiple tissue types. Aim 1 it to characterize the extensive pleiotropy and allelic heterogeneity at 5p15.33 by conducting co-localization analyses and fine mapping across multiple phenotypes, leveraging multi-ancestry individual-level data and summary statistics for >15 cancer types, >10 blood cell traits, TL, epigenetic clocks, clonal hematopoiesis, and additional phenotypes. Aim 2 is to identify effects of 5p15.33 variants on gene regulation using multi-omic cis- QTLs in induced pluripotent stem cells and ‘heterogeneous differentiating cultures’, leveraging internal resources. We will also determine if 5p15.33 variants influence local mutability at the TERT mutation hotspot (using TCGA tumor data) or genome-wide mutation burden (using data from cancer-free GTEx tissues). Aim 3 is to assess the roles of TL and TL-associated variants beyond 5p15.33 in risk for somatic events, biological aging, and cancer using (1) tissue-specific TL, mutation, and epigenetic data from GTEx and (2) Mendelian randomization and genetic correlation approaches applied large-scale genetic association data. Our team has extensive expertise related to cancer, telomeres, QTL mapping, stem and differentiating cell culture, and cancer GWAS and fine mapping. We routinely work with the datasets relevant to this proposal, and we contributed to their creation, including cancer and TL GWAS, TL in diverse tissue types, and multi-omic QTLs, making us exceptionally well positioned to complete our aims. The results of this project will allow us to build a stronger scientific foundation for the role of TERT and TL in cancer susceptibility, aging, and human health.