A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.
A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.
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DOI：
10.1038/nature19823
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发表时间：
2016-10-20
期刊：
影响因子：
64.8
通讯作者：
Gallinger S
中科院分区：
文献类型：
--
作者：
Notta F;Chan-Seng-Yue M;Lemire M;Li Y;Wilson GW;Connor AA;Denroche RE;Liang SB;Brown AM;Kim JC;Wang T;Simpson JT;Beck T;Borgida A;Buchner N;Chadwick D;Hafezi-Bakhtiari S;Dick JE;Heisler L;Hollingsworth MA;Ibrahimov E;Jang GH;Johns J;Jorgensen LG;Law C;Ludkovski O;Lungu I;Ng K;Pasternack D;Petersen GM;Shlush LI;Timms L;Tsao MS;Wilson JM;Yung CK;Zogopoulos G;Bartlett JM;Alexandrov LB;Real FX;Cleary SP;Roehrl MH;McPherson JD;Stein LD;Hudson TJ;Campbell PJ;Gallinger S
胰腺癌（PC）是一种高度侵袭性的肿瘤类型，预后普遍较差，是基于逐步进展的癌症发展的经典观点的一个例子。目前的进展模型，基于对胰腺上皮内肿瘤（PanINs）病变的前体病变的分析，做出了两个预测：1)PC通过特定的遗传改变序列（KRAS > CDKN2A > TP53/SMAD4）发展；2)每一次蚀变都是独立获得的，其演化轨迹是渐进的。这个近二十年的争论的一个缺点是，克隆扩大的前体病变已被确定，并不总是属于肿瘤谱系，这表明肿瘤谱系和前体病变的进化轨迹可能是不同的。这种流行的肿瘤发生观点促成了临床观念，即PC发展缓慢，出现在晚期。然而，这种疾病的快速转移倾向和无法改善患者的预后，尽管努力旨在早期发现，认为PC的进展绝不是渐进的。通过使用新的信息学工具跟踪肿瘤富集基因组的DNA拷贝数变化及其相关重排，我们发现PC肿瘤的发生既不是渐进的，也不遵循公认的突变顺序。三分之二的肿瘤含有与有丝分裂错误相关的复杂重排模式，与间断平衡作为主要进化轨迹相一致。在一小部分病例中，这种错误的结果是同时而不是顺序地敲除典型的肿瘤前遗传驱动因素，这些驱动因素可能会阻止侵袭性癌症的生长。这些发现挑战了目前的PC肿瘤发生模型，并为引起这些侵袭性肿瘤的突变过程提供了新的见解。
Pancreas cancer (PC), a highly aggressive tumour type with uniformly poor prognosis, is an exemplar of the classical view of cancer development based on stepwise progression. The current progression model, based on analyses of precursor lesions termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: 1) PC develops through a particular sequence of genetic alterations (KRAS > CDKN2A > TP53/SMAD4); and 2) the evolutionary trajectory of PC progression is gradual because each alteration is acquired independently. One shortcoming of this nearly two decade old contention is that clonally expanded precursor lesions have been identified that do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing view of tumourigenesis has contributed to the clinical notion that PC evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes despite efforts aimed at early detection, argue that PC progression is anything but gradual. By tracking DNA copy number changes and their associated rearrangements from tumour-enriched genomes using novel informatics tools, we found that PC tumourigenesis neither is gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors was the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that likely set-off invasive cancer growth. These findings challenge the current model of PC tumourigenesis and provide novel insights into the mutational processes giving rise to these aggressive tumours.