Molecular correlates of metastasis by systematic pan-cancer analysis across The Cancer Genome Atlas.

Tumor metastasis is a major contributor to cancer patient mortality, but the process remains poorly understood. Molecular comparisons between primary tumors and metastases can provide insights into the pathways and processes involved. Here, we systematically analyzed and cataloged molecular correlates of metastasis using The Cancer Genome Atlas (TCGA) datasets across 11 different cancer types, these data involving 4,473 primary tumor samples and 395 tumor metastasis samples (including 369 from melanoma). For each cancer type, widespread differences in gene transcription between primary and metastasis samples were observed. For several cancer types, metastasis-associated genes from TCGA comparisons were found to overlap extensively with external results from independent profiling datasets of metastatic tumors. While some differential expression patterns associated with metastasis were found to be shared across multiple cancer types, by and large each cancer type showed a metastasis signature that was distinctive from those of the other cancer types. Functional categories of genes enriched in multiple cancer type-specific metastasis over-expression signatures included cellular response to stress, DNA repair, oxidation-reduction process, protein deubiquitination, and receptor activity. The TCGA-derived prostate cancer metastasis signature in particular could define a subset of aggressive primary prostate cancer. Transglutaminase 2 protein and mRNA were both elevated in metastases from breast and melanoma cancers. Alterations in microRNAs and in DNA methylation were also identified. Implications: Our findings suggest that there are different molecular pathways to metastasis involved in different cancers. Our catalog of alterations provides a resource for future studies investigating the role of specific genes in metastasis.