Pearlman Alexander, Upadhyay Kinnari, Cole Kim, Loke John, Sun Katherine, Fineberg Susan, Freedland Stephen J, Shao Yongzhao, Ostrer Harry
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Pathology, NYU School of Medicine, New York, NY, USA.
Genes Cancer. 2018 Jan;9(1-2):66-77. doi: 10.18632/genesandcancer.165.
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.
拷贝数改变（CNAs）是在许多癌症中观察到的最常见的基因变化，反映了这种疾病固有的染色体不稳定性。然而，这些改变如何影响基因功能以促进不同肿瘤类型的转移尚未明确。在本研究中，我们基于观察到的CNAs开发了一种泛癌转移潜能评分（panMPS）。panMPS可预测前列腺癌、三阴性乳腺癌和肺腺癌患者队列中的转移及无转移生存期，以及Metabric乳腺癌队列和来自癌症基因组图谱（TCGA）的三个队列（包括前列腺癌、乳腺癌和肺腺癌）中的总生存期。这些CNAs存在于来自八个不同来源的转移性肿瘤细胞系中，所有细胞系的panMPS均升高即反映了这一点。许多拷贝数改变涉及包含多个基因的大染色体片段（“基因簇”）。我们表明，利用这种结构信息，每个基因簇仅选择一个基因就能捕捉该基因簇内其他基因的作用，从而形成一个强大的转移结果预测指标。这些选定的基因集与发生突变的癌症驱动基因不同，事实上，其中超过一半已发表了与转移相关的功能。
