Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Nature. 2010 Oct 28;467(7319):1114-7. doi: 10.1038/nature09515.
Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.
转移，即肿瘤细胞在起源器官以外的部位扩散和生长，是癌症患者死亡的最常见原因。这在胰腺癌中尤为如此，大多数患者被诊断为转移性疾病，很少对化疗或放疗有持续的反应。与其他类型的癌症患者相比，胰腺癌患者预后不佳是由于诊断较晚还是疾病较早扩散到远处器官尚不清楚。在这里，我们依赖于对七个胰腺癌转移灶的基因组测序所产生的数据来评估原发性和转移性癌症之间的克隆关系。我们发现，导致远处转移的克隆群体存在于原发性癌中，但这些克隆是从原始的、非转移性的亲代克隆中遗传进化而来的。因此，转移的遗传异质性反映了原发性癌中的情况。对胰腺癌遗传进化的时间进行了定量分析，表明从起始突变的发生到亲代、非转移性起始细胞的产生至少需要十年的时间。还需要至少五年的时间才能获得转移能力，此后患者平均两年内死亡。这些数据为胰腺癌进展的遗传特征提供了新的见解，并确定了一个广泛的早期检测机会窗口，以防止死于转移性疾病。
