Varna M, Soliman H, Feugeas J-P, Turpin E, Chapelin D, Legrès L, Plassa L-F, de Roquancourt A, Espié M, Misset J-L, Janin A, de Thé H, Bertheau P
INSERM U728, University Hematology Institute, University Paris 7 Denis Diderot, Paris, France.
Br J Cancer. 2007 Oct 22;97(8):1157-64. doi: 10.1038/sj.bjc.6603937. Epub 2007 Sep 18.
In advanced breast cancers, TP53 mutation is highly predictive of complete response to high-dose epirubicin/cyclophosphamide chemotherapy. In these tumours with an altered control of genomic stability, accumulation of chemotherapy-induced genetic alterations may contribute to cell death and account for complete response. To explore the effects of chemotherapy on stability of the tumour genome, allelic profiles were obtained from microdissected tumour samples before and after chemotherapy in 29 unresponsive breast cancers (9 with TP53 mutation). Ninety-four per cent allelic profiles remained unchanged after treatment. Interestingly, 11 profiles (6%) showed important changes after treatment; allelic imbalances significantly increased (four cases) or decreased (seven cases) after chemotherapy in three distinct experiments, two of which using laser microdissected tumour cells. These genetic changes were not linked to the TP53 status, but one tumour showed complete disappearance of TP53-mutated cells in the residual tumour after treatment. Altogether, these observations carry important implications for the clonal evolution of breast cancers treated with DNA-damaging agents, as they point both to the importance of tumour heterogeneity and chemotherapy-driven selection of subclones.
在晚期乳腺癌中，TP53突变高度预示着对高剂量表柔比星/环磷酰胺化疗的完全缓解。在这些基因组稳定性控制改变的肿瘤中，化疗诱导的基因改变的积累可能导致细胞死亡并解释完全缓解的原因。为了探究化疗对肿瘤基因组稳定性的影响，从29例无反应性乳腺癌（9例有TP53突变）化疗前后的显微切割肿瘤样本中获取等位基因谱。94%的等位基因谱在治疗后保持不变。有趣的是，11个谱（6%）在治疗后显示出重要变化；在三个不同实验中，化疗后等位基因不平衡显著增加（4例）或减少（7例），其中两个实验使用激光显微切割的肿瘤细胞。这些基因变化与TP53状态无关，但有一个肿瘤在治疗后的残留肿瘤中显示TP53突变细胞完全消失。总之，这些观察结果对接受DNA损伤剂治疗的乳腺癌的克隆进化具有重要意义，因为它们既指出了肿瘤异质性的重要性，也指出了化疗驱动的亚克隆选择的重要性。
