The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Nature. 2011 Feb 10;470(7333):214-20. doi: 10.1038/nature09744.
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.
在美国，前列腺癌是男性癌症死亡的第二大常见原因。然而，前列腺癌基因组改变的全貌尚未完全描述。在这里，我们展示了七个原发性人前列腺癌及其配对正常对照物的完整序列。一些肿瘤包含了在已知癌基因内或附近发生的复杂的平衡（即“拷贝中性”）重排链，在 ETS 基因融合 TMPRSS2-ERG 的背景下，重排断点在开放染色质、雄激素受体和 ERG DNA 结合位点附近富集，但在缺乏 ETS 融合的肿瘤中与这些区域呈负相关。这一观察结果表明染色质或转录调控与基因组异常的发生之间存在联系。三个肿瘤包含破坏 CADM2 的重排，四个肿瘤则发生破坏前列腺肿瘤抑制因子 PTEN（不平衡事件）或 MAGI2（平衡事件）的事件，后者是以前未涉及前列腺肿瘤发生的 PTEN 相互作用蛋白。因此，基因组重排可能源于转录或染色质异常，并涉及前列腺肿瘤发生机制。
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