Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
Nature. 2017 Jan 19;541(7637):359-364. doi: 10.1038/nature20788. Epub 2017 Jan 9.
Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.
前列腺肿瘤对治疗的反应具有高度可变性，但临床可用的预后因素只能解释这种异质性的一小部分。在这里，我们分析了 200 个全基因组序列和 277 个局部非侵袭性前列腺肿瘤的额外全外显子序列，这些肿瘤具有相似的临床风险特征，并在亚组中进行了 RNA 和甲基化分析。与转移性疾病不同，这些肿瘤中很少有临床可操作的单核苷酸变异。相反，相当一部分肿瘤存在反复出现的非编码异常、大规模基因组重排，以及在其边界内抑制转录的反转录。局部高突变事件频繁，并与特定的基因组图谱相关。许多分子异常与疾病复发相关，包括几个 DNA 甲基化事件，并且由这些异常组成的特征明显优于描述良好的预后生物标志物。我们认为，强化治疗具有基因组侵袭性的局限性前列腺癌可能会提高治愈率。
