Christine Iacobuzio-Donahue及其同事利用全基因組“外顯子組”測(cè)序來分析來自相同患者的原發(fā)胰腺癌和一種或多種轉(zhuǎn)移腫瘤,。他們發(fā)現(xiàn)腫瘤由截然不同的亞克隆組成，確定了轉(zhuǎn)移性癌癥克隆在原發(fā)腫瘤內(nèi)演化的演化圖,，并且估計(jì)了腫瘤發(fā)展的時(shí)間尺度,。
基于這些數(shù)據(jù)他們估計(jì),，在胰腺腫瘤發(fā)生的開始和原發(fā)的、非轉(zhuǎn)移性腫瘤的形成之間的平均時(shí)間為11.8年,，而指示性轉(zhuǎn)移克隆的出現(xiàn)另需6.8年,。這些數(shù)據(jù)表明存在一個(gè)潛在很大的機(jī)會(huì)窗口，在此時(shí)段內(nèi)也許有可能相對(duì)較早地檢測(cè)出癌癥來,。
Peter Campbell及其同事利用下一代測(cè)序方法檢測(cè)了13名胰腺癌患者的染色體重排,。結(jié)果顯示患者間存在相當(dāng)大的異質(zhì)性,，表明在轉(zhuǎn)移的發(fā)生過程中基因組不穩(wěn)定和演化是持續(xù)存在的。但對(duì)所研究的大部分患者來說,，所發(fā)現(xiàn)的基因重排中超過一半存在于所有轉(zhuǎn)移腫瘤和原發(fā)腫瘤中,，從而使其成為在這種疾病的早期和晚期進(jìn)行治療干預(yù)的潛在目標(biāo)。（生物谷Bioon.com）
生物谷推薦英文摘要：
Nature doi:10.1038/nature09460
The patterns and dynamics of genomic instability in metastatic pancreatic cancer
Peter J. Campbell,Shinichi Yachida,Laura J. Mudie,Philip J. Stephens,Erin D. Pleasance,Lucy A. Stebbings,Laura A. Morsberger,Calli Latimer,Stuart McLaren,Meng-Lay Lin,David J. McBride,Ignacio Varela,Serena A. Nik-Zainal,Catherine Leroy,Mingming Jia,Andrew Menzies,Adam P. Butler,Jon W. Teague,Constance A. Griffin,John Burton,Harold Swerdlow,Michael A. Quail,Michael R. Stratton,Christine [email protected]& P. Andrew [email protected]
Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97–98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations1, 2, 3, 4, 5, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours6, 7, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites7, and how the tumour disseminates. Here we harness advances in DNA sequencing8, 9, 10, 11, 12 to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2–M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.
