Abstract
Copy number alterations(CNAs) are the most common genetic changes observed in many cancers, reflecting the innate chromosomal instability of this disorder. Yet, how these alterations affect gene function to promote metastases across different tumor types has not been established. In this study, we developed a pan-cancer metastasis potential score (panMPS) based on observed CNAs. panMPS predicts metastasis and metastasis-free survival in cohorts of patients with prostate cancer, triple negative breast cancer and lung adenocarcinoma, and overall survival in the Metabric breast cancer cohort and three cohorts from The Cancer Genome Atlas (TCGA), including prostate, breast and lung adenocarcinoma. These CNAs are present in cell lines of metastatic tumors from eight different origins, reflected by an elevated panMPS for all cell lines. Many copy number alterations involve large chromosomal segments that encompass multiple genes (“clumps”). We show that harnessing this structural information to select only one gene per clump captures the contributions of other genes within the clump, resulting in a robust predictor of metastasis outcome. These sets of selected genes are distinct from cancer drivers that undergo mutation, and in fact, metastasis-related functions have been published for over half of them.
Highlights
Tumor metastasis to distant sites accounts for 90% of solid tumor cancer deaths [1]
We developed a metastatic potential score (MPS) that was based on the weighted frequency of specific CNA pattern in the 366 genes observed in prostate cancer metastases [4]
The validity of pan-cancer metastasis potential score (panMPS) as a predictor of metastasis outcome was tested in studies of primary tumors, including prostate cancer, triple negative breast cancer and lung adenocarcinoma
Summary
Tumor metastasis to distant sites accounts for 90% of solid tumor cancer deaths [1]. The frequency with which metastasis occurs varies by tumor type, and even within a tumor type the time between diagnosis to metastasis can be quite variable. Many of the steps involved in the development of metastasis are shared across tumor types, including detachment from the matrix of origin and evasion of apoptosis, invasion beyond the site of origin, and colonization of distant sites. These steps are genetically encoded [2]. A study from our laboratory showed that despite the high frequency of these CNAs throughout the genome, 366 genes within these regions were commonly altered with similar amplification and deletion patterns in prostate cancer metastases and primary tumors that progress to metastases [4]. The remaining 35% of the genes (125 of 366) were observed as singletons
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