Shelterin, a protective complex at telomeres, plays essential roles in
cancer. In addition to maintain telomere integrity, shelterin functions in various survival pathways. However, the detailed mechanisms of shelterin regulation in
cancer remain elusive. Here, we perform a comprehensive analysis of shelterin in 9125
tumor samples across 33
cancer types using multi-omic data from The
Cancer Genome Atlas, and validate some findings in Chinese
Glioma Genome Atlas and
cancer cell lines from
Cancer Cell Line Encyclopedia. In the genomic landscape, we identify the amplification of TRF1 and POT1, co-amplification/deletion of TRF2-RAP1-TPP1 as the dominant alteration events. Clustering analysis based on shelterin expression reveals three
cancer clusters with different degree of
genome instability. To measure overall shelterin activity in
cancer, we derive a shelterin score based on shelterin expression. Pathway analysis shows shelterin is positively correlated with E2F targets, while is negatively correlated with p53 pathway. Importantly, shelterin links to
tumor immunity and predicts response to PD-1 blockade immune
therapy. In-depth
miRNA analysis reveals a
miRNA-shelterin interaction network, with p53 regulated
miRNAs targeting multiple shelterin components. We also identify a significant amount of lncRNAs regulating shelterin expression. In addition, we find shelterin expression could be used to predict patient survival in 24
cancer types. Finally, by mining the connective map database, we discover a number of potential drugs that might target shelterin. In summary, this study provides broad molecular signatures for further functional and therapeutic studies of shelterin, and also represents a systemic approach to characterize key
protein complex in
cancer.