Torres Lurdes, Ribeiro Franclim R, Pandis Nikos, Andersen Johan A, Heim Sverre, Teixeira Manuel R
Department of Genetics, Portuguese Oncology Institute, Rua Dr António Bernardino de Almeida, Porto, Portugal.
Breast Cancer Res Treat. 2007 Apr;102(2):143-55. doi: 10.1007/s10549-006-9317-6. Epub 2006 Aug 9.
Conflicting theories of epithelial carcinogenesis disagree on the clonal composition of primary tumors and on the time at which metastases occur. In order to study the spatial distribution of disparate clonal populations within breast carcinomas and the extent of the genetic relationship between primary tumors and regional metastases, we have analyzed by comparative genomic hybridization 122 tissue samples from altogether 60 breast cancer patients, including 34 tumor samples obtained from different quadrants of 9 breast carcinomas, as well as paired primary-metastatic samples from 12 patients. The median intratumor genetic heterogeneity score (HS) was 17.4% and unsupervised hierarchical clustering analysis comparing the genetic features to those of an independent series of 41 breast carcinomas confirmed intratumor clonal divergence in a high proportion of cases. The median HS between paired primary breast tumors and lymph node metastases was 33.3%, but the number of genomic imbalances did not differ significantly. Clustering analysis confirmed extensive clonal divergence between primary carcinomas and lymph node metastases in several cases. In the independent series of 41 breast carcinomas, the number of genomic imbalances in primary tumors was significantly higher in patients presenting lymph node metastases (median = 15.5) than in the group with no evidence of disease spreading at diagnosis (median = 5.0). We conclude that primary breast carcinomas may be composed of several genetically heterogeneous and spatially separated cell populations and that paired primary breast tumors and lymph node metastases often present divergent clonal evolution, indicating that metastases may occur relatively early during breast carcinogenesis.
上皮癌发生的相互冲突的理论在原发性肿瘤的克隆组成以及转移发生的时间上存在分歧。为了研究乳腺癌内不同克隆群体的空间分布以及原发性肿瘤与区域转移之间的遗传关系程度，我们通过比较基因组杂交分析了来自60例乳腺癌患者的共122个组织样本，包括从9例乳腺癌的不同象限获取的34个肿瘤样本，以及12例患者的配对原发性 - 转移性样本。肿瘤内遗传异质性评分（HS）的中位数为17.4%，将遗传特征与41例乳腺癌的独立系列进行比较的无监督层次聚类分析证实，在高比例的病例中存在肿瘤内克隆分歧。配对的原发性乳腺肿瘤与淋巴结转移之间的HS中位数为33.3%，但基因组不平衡的数量没有显著差异。聚类分析证实，在一些病例中，原发性癌与淋巴结转移之间存在广泛的克隆分歧。在41例乳腺癌的独立系列中，出现淋巴结转移的患者原发性肿瘤中的基因组不平衡数量（中位数 = 15.5）显著高于诊断时无疾病扩散证据的组（中位数 = 5.0）。我们得出结论，原发性乳腺癌可能由几个基因异质性且空间上分离的细胞群体组成，并且配对的原发性乳腺肿瘤与淋巴结转移通常呈现出不同的克隆进化，这表明转移可能在乳腺癌发生过程中相对较早地发生。
