Evolution of neoplastic cell lineages in Barrett oesophagus
Evolution of neoplastic cell lineages in Barrett oesophagus
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DOI：
10.1038/8816
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发表时间：
1999-05-01
期刊：
影响因子：
30.8
通讯作者：
Reid, BJ
中科院分区：
文献类型：
--
作者：
Barrett, MT;Sanchez, CA;Reid, BJ
据推测，肿瘤进展的发展是获得性遗传不稳定性和随后的克隆种群进化积累遗传错误的结果1。因此，人类癌症和一些癌前病变包含多种遗传异常，而这些遗传异常不存在于产生肿瘤的正常组织中2，3。巴雷特食管（BE）是一种癌前病变，易患食管腺癌（EA），随着时间的推移，可以前瞻性地进行活检，因为内镜监测被推荐用于癌症的早期检测4，5。此外，食管切除术标本经常含有癌前上皮，癌发生6。BE的肿瘤进展与TP 53（也称为p53）和CDKN 2A（也称为p16）的改变以及杂合性7、8、9、10、11（洛）的非随机丢失相关。非整倍体或增加的4 N群体发生在超过90-95%的EA中，出现在癌前上皮中并预测进展10，12，13。我们先前已经在少数患者中显示，TP 53和CDKN 2A的破坏通常发生在非整倍性和癌症之前10，11，14，15。在这里，我们确定了肿瘤进展过程中非随机洛缺失、TP 53和CDKN 2A突变、CDKN 2A CpG岛甲基化和倍性的进化关系。在TP 53和CDKN 2A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克隆扩增，扩散到食管粘膜的大区域。肿瘤后代的后续演变经常涉及在5 q、13 q和18 q的分叉和洛缺失，其相对于彼此、DNA含量非整倍体或癌症没有必然的顺序发生。我们的研究结果表明，克隆进化比线性模型预测的更复杂。
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 1. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose 2, 3. 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 4, 5. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose 6. 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 7, 8, 9, 10, 11 (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression 10, 12, 13. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer 10, 11, 14, 15. 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.