Barrett M T, Sanchez C A, Prevo L J, Wong D J, Galipeau P C, Paulson T G, Rabinovitch P S, Reid B J
Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.
Nat Genet. 1999 May;22(1):106-9. doi: 10.1038/8816.
It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models.
据推测，肿瘤进展是由于获得性基因不稳定以及随后具有累积基因错误的克隆群体的进化所致。因此，人类癌症和一些癌前病变包含肿瘤起源的正常组织中不存在的多种基因异常。巴雷特食管（BE）是一种癌前病变，易患食管腺癌（EA），由于建议进行内镜监测以早期发现癌症，因此可以随着时间的推移进行前瞻性活检。此外，食管切除标本通常包含癌症起源的癌前上皮。BE中的肿瘤进展与TP53（也称为p53）和CDKN2A（也称为p16）的改变以及非随机性杂合性缺失（LOH）有关。超过90-95%的EA中出现非整倍体或增加的4N群体，出现在癌前上皮中并预测进展。我们之前在少数患者中表明，TP53和CDKN2A的破坏通常发生在非整倍体和癌症之前。在这里，我们确定了肿瘤进展过程中非随机性LOH、TP53和CDKN2A突变、CDKN2A CpG岛甲基化和倍性之间的进化关系。在TP53和CDKN2A中具有体细胞遗传或表观遗传异常的二倍体细胞祖细胞能够进行克隆扩增，扩散到食管黏膜的大片区域。肿瘤后代的后续进化经常涉及5q、13q和18q处的分叉和LOH，它们彼此之间没有必然的顺序，DNA含量非整倍体或癌症。我们的结果表明，克隆进化比线性模型预测的更为复杂。
