Histopathology Laboratory, London Research Institute, Cancer Research UK, London, UK.
Gastroenterology. 2011 Apr;140(4):1251-1260.e1-6. doi: 10.1053/j.gastro.2010.12.051. Epub 2011 Jan 9.
BACKGROUND & AIMS: Studies of the clonal architecture of gastric glands with intestinal metaplasia are important in our understanding of the progression from metaplasia to dysplasia. It is not clear if dysplasias are derived from intestinal metaplasia or how dysplasias expand. We investigated whether cells within a metaplastic gland share a common origin, whether glands clonally expand by fission, and determine if such metaplastic glands are genetically related to the associated dysplasia. We also examined the clonal architecture of entire dysplastic lesions and the genetic changes associated with progression within dysplasia.
Cytochrome c oxidase-deficient (CCO⁻) metaplastic glands were identified using a dual enzyme histochemical assay. Clonality was assessed by laser capture of multiple cells throughout CCO⁻ glands and polymerase chain reaction sequencing of the entire mitochondrial DNA (mtDNA) genome. Nuclear DNA abnormalities in individual glands were identified by laser capture microdissection polymerase chain reaction sequencing for mutation hot spots and microsatellite loss of heterozygosity analysis.
Metaplastic glands were derived from the same clone-all lineages shared a common mtDNA mutation. Mutated glands were found in patches that had developed through gland fission. Metaplastic and dysplastic glands can be genetically related, indicating the clonal origin of dysplasia from metaplasia. Entire dysplastic fields contained a founder mutation from which multiple, distinct subclones developed.
There is evidence for a distinct clonal evolution from metaplasia to dysplasia in the human stomach. By field cancerization, a single clone can expand to form an entire dysplastic lesion. Over time, this field appears to become genetically diverse, indicating that gastric cancer can arise from a subclone of the founder mutation.
研究具有肠上皮化生的胃腺克隆结构对于理解化生向异型增生的进展非常重要。异型增生是否来源于肠上皮化生，以及异型增生如何扩展尚不清楚。我们研究了肠化生腺体内的细胞是否具有共同的起源，腺是否通过分裂进行克隆性扩张，以及这种肠化生腺是否与相关的异型增生具有遗传相关性。我们还检查了整个异型增生病变的克隆结构以及异型增生内进展相关的遗传变化。
使用双酶组织化学测定法鉴定细胞色素 c 氧化酶缺陷（CCO⁻）化生腺。通过激光捕获 CCO⁻腺体内的多个细胞并对整个线粒体 DNA（mtDNA）基因组进行聚合酶链反应测序来评估克隆性。通过激光捕获微切割聚合酶链反应测序鉴定个体腺体内的核 DNA 异常，以进行突变热点和微卫星杂合性丢失分析。
化生腺来源于同一克隆-所有谱系均共享共同的 mtDNA 突变。突变的腺位于通过腺分裂形成的斑块中。化生和异型增生腺可以具有遗传相关性，表明异型增生来源于化生的克隆起源。整个异型增生灶均含有一个起始突变，多个不同的亚克隆由此发展而来。
人类胃中存在从化生到异型增生的明确克隆进化证据。通过“肿瘤异质性”，单个克隆可以扩展形成整个异型增生病变。随着时间的推移，该病灶似乎变得具有遗传多样性，表明胃癌可能起源于起始突变的亚克隆。
