Kuukasjärvi T, Karhu R, Tanner M, Kähkönen M, Schäffer A, Nupponen N, Pennanen S, Kallioniemi A, Kallioniemi O P, Isola J
Department of Pathology, Tampere University Hospital, University of Tampere, Finland.
Cancer Res. 1997 Apr 15;57(8):1597-604.
To understand the genetic basis and clonal evolution underlying metastatic progression of human breast cancer in vivo, we analyzed the genetic composition of 29 primary breast carcinomas and their paired asynchronous metastases by comparative genomic hybridization and fluorescence in situ hybridization. The mean number of genetic changes by comparative genomic hybridization was 8.7 +/- 5.3 in primary tumors and 9.0 +/- 5.7 in their metastases. Although most of the genetic changes occurred equally often in the two groups, gains of the Xq12-q22 region were enriched in the metastases. According to a statistical analysis of shared genetic changes and breakpoints in paired specimens, 20 of the metastases (69%) showed a high degree of clonal relationship with the corresponding primary tumor, whereas the genetic composition of 9 metastases (31%) differed almost completely from that of the paired primary tumors. In both groups, however, chromosome X inactivation patterns suggested that the metastatic lesions originated from the same clone as the primary tumor. Fluorescence in situ hybridization analysis with probes specific to metastatic clones usually failed to find such cells in the primary tumor sample. In conclusion, detailed characterization of the in vivo progression pathways of metastatic breast cancer indicates that a linear progression model is unlikely to account for the progression of primary tumors to metastases. An early stem line clone apparently evolves independently in the primary tumor and its metastasis, eventually leading to multiple, genetically almost completely different, clones in the various tumor locations in a given patient. The resulting heterogeneity of metastatic breast cancer may underlie its poor responsiveness to therapy and explain why biomarkers of prognosis or therapy responsiveness measured exclusively from primary tumors give a restricted view of the biological properties of metastatic breast cancer.
为了解人类乳腺癌在体内转移进展的遗传基础和克隆进化，我们通过比较基因组杂交和荧光原位杂交分析了29例原发性乳腺癌及其配对的不同时相转移灶的基因组成。原发性肿瘤通过比较基因组杂交检测到的基因改变平均数为8.7±5.3，其转移灶为9.0±5.7。虽然大多数基因改变在两组中出现的频率相同，但Xq12 - q22区域的扩增在转移灶中更为富集。根据对配对样本中共享基因改变和断点的统计分析，20个转移灶（69%）与相应的原发性肿瘤显示出高度的克隆关系，而9个转移灶（31%）的基因组成与配对的原发性肿瘤几乎完全不同。然而，在两组中，X染色体失活模式表明转移灶与原发性肿瘤起源于同一克隆。用针对转移克隆的特异性探针进行荧光原位杂交分析通常在原发性肿瘤样本中找不到此类细胞。总之，对转移性乳腺癌体内进展途径的详细表征表明，线性进展模型不太可能解释原发性肿瘤向转移灶的进展。一个早期的干细胞系克隆显然在原发性肿瘤及其转移灶中独立进化，最终在给定患者的不同肿瘤部位导致多个基因上几乎完全不同的克隆。转移性乳腺癌产生的这种异质性可能是其对治疗反应不佳的基础，并解释了为什么仅从原发性肿瘤测量的预后或治疗反应生物标志物只能有限地反映转移性乳腺癌的生物学特性。
