The genomic complexity of primary human prostate cancer

作者：Michael F. Berger, Michael S. Lawrence, Francesca Demichelis, Yotam Drier, Kristian Cibulskis, Andrey Sivachenko, Andrea Sboner, Raquel Esgueva, Dorothee Pflueger, Carrie L. Sougnez, Robert C. Onofrio, Scott L. Carter, Kyung Park, Lukas Habegger, Lauren Ambrogio, Timothy R. Fennell, Melissa Parkin, Gordon Saksena, Douglas Voet, Alex H. Ramos, Trevor J. Pugh, Jane Wilkinson, Sheila A. Fisher, Wendy Winckler, Scott P. Mahan, Kristin Ardlie, Jennifer Baldwin, Jonathan W. Simons, Naoki Kitabayashi, Theresa Y. MacDonald, Philip W. Kantoff, Lynda Chin, Stacey L. Gabriel, Mark Gerstein, Todd R. Golub, Matthew M. Meyerson, Ashutosh Kumar Tewari, Eric S. Lander, Gad A. Getz, Mark Andrew Rubin, Levi A. Garraway · 发表于：Nature · 年份：2011 · DOI：10.1038/nature09744 · 被引用次数：1262 · 研究领域：Prostate Cancer Treatment and Research、Cancer-related molecular mechanisms research、Cancer Genomics and Diagnostics

Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, ‘copy-neutral’) rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2–ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms. Prostate cancer is a common cause of male cancer-related deaths. Complete genome sequencing of seven 'high-risk' primary prostate cancers and their paired normal counterparts now reveals previously unknown balanced rearrangements, at which multiple intra- and inter-chromosomal loci exchange their...