Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village 404-406, SE22363 Lund, Sweden.
Nat Commun. 2015 Jan 27;6:6125. doi: 10.1038/ncomms7125.
Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.
同一肿瘤内的肿瘤细胞的遗传差异被认为是推动癌症进展和治疗失败的原因。关于肿瘤内异质性的数据是否可以用于预测临床结果尚不清楚。我们通过定量分析一组化疗治疗的儿童肿瘤中的遗传肿瘤内异质性来解决这个问题。通过对 7 名患者的多个肿瘤样本进行分析，我们证明了所有接受化疗后的患者都存在肿瘤内异质性，通常表现为单个毫米大小的肿瘤样本内的多个克隆（微异质性）。我们表明，微异质性通常是转移中进一步基因组进化的基础。此外，我们发现微异质性预测了 44 名接受化疗治疗的儿童肾癌患者队列中的不良癌症特异性生存（60%；P=0.009），独立于其他风险因素。缺乏微异质性的患者的生存率为 100%。因此，化疗后儿童癌症中常见肿瘤内遗传多样性，并且可能是治疗失败背后的重要因素。
