Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
Genes Chromosomes Cancer. 2012 Jun;51(6):579-89. doi: 10.1002/gcc.21944. Epub 2012 Feb 15.
Many human cancers present as multifocal lesions. Understanding the clonal origin of multifocal cancers is of both etiological and clinical importance. The molecular basis of multifocal prostate cancer has previously been explored using a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multifocal prostate cancer is still debatable. We attempted to address clonal origin using a genome-wide copy-number analysis of individual cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) lesions. Using Affymetrix array 6.0 copy-number analysis, we compared the genomic changes detected in 48 individual cancer and HGPIN lesions, isolated from 18 clinically localized prostate cancer cases. Identical genomic copy-number changes, shared by all same-case cancer foci, were detected in all 13 informative cases displaying multiple tumor foci. In addition, individual HGPIN lesions in the two multifocal-HGPIN cases available shared identical genomic changes. Commonly known genomic alterations, including losses at 6q15, 8p21.3-8p21.2, 10q23.2-10q23.31, 16q22.3, 16q23.2-16q23.3 and 21q22.2-21q22.3 regions and gain of 8q24.3 were the most frequently detected changes in this study and each was detected in all same-case foci in at least one case. Microarray data were confirmed by fluorescence in situ hybridization in selected foci. Our high-resolution genome-wide copy-number data suggest that many multifocal cases derive from a single prostate cancer precursor clone and that this precursor may give rise to separate HGPIN foci and may further progress to multifocal invasive prostate cancer. These findings, which demonstrate the monoclonal origin of multifocal prostate cancer, should significantly enhance our understanding of prostate carcinogenesis.
许多人类癌症表现为多灶性病变。了解多灶性癌症的克隆起源具有病因学和临床重要性。以前已经使用有限数量的分离标记物探索了多灶性前列腺癌的分子基础，尽管普遍认为起源是独立的，但多灶性前列腺癌的克隆起源仍存在争议。我们试图使用个体癌症和高级前列腺上皮内瘤变（HGPIN）病变的全基因组拷贝数分析来解决克隆起源问题。使用 Affymetrix 阵列 6.0 拷贝数分析，我们比较了从 18 例临床局限性前列腺癌病例中分离出的 48 个单独癌症和 HGPIN 病变的基因组变化。在所有 13 个显示多个肿瘤灶的信息丰富的病例中，均检测到了所有相同病例癌症灶共有的相同基因组拷贝数变化。此外，在两个多灶性 HGPIN 病例中，个别 HGPIN 病变共享相同的基因组变化。在这项研究中，最常检测到的常见基因组改变包括 6q15、8p21.3-8p21.2、10q23.2-10q23.31、16q22.3、16q23.2-16q23.3 和 21q22.2-21q22.3 区域的缺失以及 8q24.3 的获得，并且每个区域都至少在一个病例的所有相同病例灶中检测到。微阵列数据在选定的焦点中通过荧光原位杂交得到证实。我们的高分辨率全基因组拷贝数数据表明，许多多灶性病例源自单个前列腺癌前体克隆，该前体可能导致单独的 HGPIN 灶，并可能进一步发展为多灶性浸润性前列腺癌。这些发现证明了多灶性前列腺癌的单克隆起源，应大大增强我们对前列腺癌发生的理解。
