Abstract
Aging modifies risk in all cancers, but age is used as a clinical staging criterion uniquely in thyroid cancer (TC). The molecular drivers of age-dependent TC onset and aggressiveness remain poorly understood. We applied an integrative, multi-omics data analysis approach to characterize these signatures. Our analysis reveals that aging, independent of BRAF(V600E) mutational status, drives a significant accumulation of aggressiveness-related markers and poorer survival outcomes, most noticeably at age 55 and over. We identified that chromosomal alterations in loci 1p/1q as aging-associated drivers of aggressiveness, and that depleted infiltration with tumor surveillant CD8+T and follicular helper T cells, dysregulation of proteostasis- and senescence-related processes, and ERK1/2 signaling cascade are key features of the aging thyroid and TC onset/progression and aggressiveness in aging patients but not in young individuals. A panel of 23 genes, including those related to cell division such as CENPF, ERCC6L, and the kinases MELK and NEK2, were identified and rigorously characterized as aging-dependent and aggressiveness-specific markers. These genes effectively stratified patients into aggressive clusters with distinct phenotypic enrichment and genomic/transcriptomic profiles. This panel also showed excellent performance in predicting metastasis stage, BRAF(V600E), TERT promoter mutation, and survival outcomes and was superior to the American Thyroid Association (ATA) methodology in predicting aggressiveness risk. Our analysis established clinically relevant biomarkers for TC aggressiveness factoring in aging as an important component.