Califano J, Westra W H, Meininger G, Corio R, Koch W M, Sidransky D
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, Maryland 21204, USA.
Clin Cancer Res. 2000 Feb;6(2):347-52.
We constructed a preliminary genetic progression model for head and neck squamous cell carcinoma (HNSC) based on the frequency of genetic alterations in preneoplastic and neoplastic lesions from single biopsy specimens. To firmly establish the temporal order of established genetic events in HNSC, we sampled serial biopsies from five patients with recurrent premalignant lesions at a single anatomic site over a period of time (1 month to 144 months). These lesions were examined by microsatellite analysis of the minimal regions of loss on the 10 most frequently lost chromosomal arms in HNSC. Each set of serial biopsies from all five patients demonstrated LOH (loss of heterozygosity) of identical alleles at multiple loci with identical boundaries between areas of LOH and retention of heterozygosity, indicating a common clonal origin for each set. Three patients demonstrated genetic progression (new regions of LOH) over time correlating with histopathological progression, one patient demonstrated lack of genetic progression associated with unchanged histopathological morphology, and one patient demonstrated histopathological progression without detection of a corresponding genetic progression event. For one of these patients with a laryngeal tumor, at least four separate steps in progression to malignancy could be determined, accompanied by spatial expansion of an increasingly altered clonal population from the ipsilateral to the contralateral side, ultimately resulting in a malignancy. Microsatellite-based genetic analysis of recurrent premalignant lesions indicates that these lesions arise from a common clonal progenitor, followed by outgrowth of clonal populations associated with progressive genetic alterations and phenotypic progression to malignancy.
我们基于单个活检标本中癌前病变和肿瘤病变的基因改变频率，构建了头颈部鳞状细胞癌（HNSC）的初步遗传进展模型。为了牢固确立HNSC中已确定的遗传事件的时间顺序，我们在一段时间内（1个月至144个月），从5例在单个解剖部位出现复发性癌前病变的患者中采集了系列活检样本。通过对HNSC中10条最常发生缺失的染色体臂上的最小缺失区域进行微卫星分析，对这些病变进行了检查。来自所有5例患者的每组系列活检样本均显示，在多个位点存在相同等位基因的杂合性缺失（LOH），且LOH区域与杂合性保留区域之间具有相同边界，这表明每组样本都有共同的克隆起源。3例患者随着时间推移出现了与组织病理学进展相关的遗传进展（新的LOH区域），1例患者显示出缺乏遗传进展且组织病理学形态未改变，1例患者显示出组织病理学进展但未检测到相应的遗传进展事件。对于其中1例患有喉肿瘤的患者，可以确定至少四个向恶性肿瘤进展的独立步骤，同时伴随着克隆群体从同侧到对侧的空间扩展，且改变程度越来越大，最终发展为恶性肿瘤。对复发性癌前病变进行基于微卫星的遗传分析表明，这些病变起源于共同的克隆祖细胞，随后伴随着与渐进性基因改变和向恶性肿瘤的表型进展相关的克隆群体的生长。
