CLONAL ORIGIN OF EPITHELIAL OVARIAN-CARCINOMA - ANALYSIS BY LOSS OF HETEROZYGOSITY, P53-MUTATION, AND X-CHROMOSOME INACTIVATION
CLONAL ORIGIN OF EPITHELIAL OVARIAN-CARCINOMA - ANALYSIS BY LOSS OF HETEROZYGOSITY, P53-MUTATION, AND X-CHROMOSOME INACTIVATION
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DOI：
10.1093/jnci/84.23.1793
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发表时间：
1992-12-02
期刊：
影响因子：
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通讯作者：
BAST, RC
中科院分区：
文献类型：
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作者：
JACOBS, IJ;KOHLER, MF;BAST, RC
背景：腹膜表面多部位上皮性卵巢癌反映的是腹膜间皮多原发癌引起的多克隆性疾病，而不是一种原发卵巢癌通过转移而扩散的单克隆性疾病。目的：本研究的目的是探讨卵巢癌是否具有单克隆性或多克隆性起源。方法：从17例卵巢上皮性癌患者的外周血淋巴细胞(正常DNA)和多发性肿瘤沉淀物(原发肿瘤、转移性肿瘤和腹水)中提取DNA样本。通过执行(A)分析以检测5、11、13和17号染色体上rive基因座的杂合性丢失；(B)对p53基因的外显子5-8进行测序；以及(C)对磷酸甘油酸激酶(PGK)基因进行X染色体失活分析，确定每个肿瘤的克隆性起源。结果：在分析的17例中，有15例有明确的单克隆性起源的证据。这15例中记录的遗传事件作为独立事件出现在每个肿瘤沉积中的概率从2.5x10(-1)到3.7x10(-16)。在两个病例中，等位基因缺失和p53基因突变的模式与单克隆性来源或来自两个原发卵巢肿瘤的来源一致。结论：研究结果并不支持卵巢癌是一种多部位、多克隆疾病的假设。相反，这些数据表明，散发性卵巢上皮癌要么是单克隆性起源，要么是双原发源。这些发现对于了解卵巢癌的自然病史以及旨在预防和早期发现的临床策略具有重要的意义。需要进一步的研究来确定家族性遗传性卵巢癌的克隆起源。
Background: It has been suggested that multiple sites of epithelial ovarian carcinoma on the peritoneal surface reflect polyclonal disease arising from multiple primary tumors in the peritoneal mesothelium, rather than monoclonal disease spread by metastases from one primary ovarian cancer. Purpose: The purpose of this study was to investigate whether ovarian cancer has a monoclonal or polyclonal origin. Methods: DNA specimens were obtained from peripheral blood lymphocytes (normal DNA) and from multiple tumor deposits of 17 women with epithelial ovarian carcinoma: primary tumors, metastatic deposits, and ascites. The clonal origin of each tumor was determined by performing (a) analysis to detect loss of heterozygosity at rive loci on chromosomes 5, 11, 13, and 17; (b) sequencing of exons 5-8 of the p53 gene; and (c) X-chromosome inactivation analysis of the phosphoglycerate kinase (PGK) gene. Results: In 15 of the 17 cases analyzed, there was clear evidence of monoclonal origin. The probability that the genetic events documented in these 15 cases occurred as independent events in each tumor deposit ranged from 2.5 x 10(-1) to 3.7 x 10(-16). In two cases, the pattern of allelic deletion and p53 gene mutation was compatible with either a monoclonal origin or origin from two primary ovarian tumors. Conclusions: The results did not support the hypothesis that ovarian cancer is a multifocal, polyclonal disease. Instead, the data suggest that sporadic epithelial ovarian carcinoma has either a monoclonal or a dual primary origin. Implications: These findings have important implications for understanding of the natural history of ovarian cancer and for clinical strategies aimed at prevention and early detection. Further studies will be required to determine the clonal origin of familial hereditary ovarian cancer.