Yustein A S, Harper J C, Petroni G R, Cummings O W, Moskaluk C A, Powell S M
Division of Gastroenterology and Hepatology, University of Virginia Health Sciences Center, Charlottesville 22908-0013, USA.
Cancer Res. 1999 Apr 1;59(7):1437-41.
Gastric adenocarcinoma is a leading cause of cancer mortality world-wide. Yet, the underlying molecular events important in the development of this cancer are largely undefined. Thus, we performed a comprehensive survey for allelic loss on our panel of xenografted human gastric carcinomas. Contaminating normal stromal cells of primary cancers often limit mutational analyses. Xenografted samples of our gastric carcinomas provided optimally enriched tumors for neoplasia that clearly and sensitively demonstrated genetic alterations. Additionally, total absence of allelic signals in these xenografted samples confirmed true loss of alleles rather than just allelic imbalance. Analysis of at least two highly polymorphic microsatellite markers per nonacrocentric chromosomal arm in our xenografted human gastric carcinomas demonstrated significant loss of heterozygosity well above background levels at 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q. Several of these loci represent novel findings of significant loss in gastric cancers. On chromosome 17p, p53 is known to be inactivated either by mutation or deletion in a majority of gastric carcinomas. The critical target(s) of inactivation in gastric cancers at these other loci remain to be characterized.
胃腺癌是全球癌症死亡的主要原因。然而，这种癌症发生过程中重要的潜在分子事件在很大程度上仍不明确。因此，我们对一组异种移植的人类胃癌进行了等位基因缺失的全面调查。原发性癌症中混杂的正常基质细胞常常限制突变分析。我们的胃癌异种移植样本为肿瘤形成提供了最佳富集的肿瘤，能清晰且灵敏地显示基因改变。此外，这些异种移植样本中完全没有等位基因信号证实了等位基因的真正缺失，而不仅仅是等位基因失衡。对我们异种移植的人类胃癌中每个非近端着丝粒染色体臂至少两个高度多态性微卫星标记的分析表明，在3p、4p、5q、8p、9p、13q、17p和18q处杂合性显著丧失，远高于背景水平。其中几个位点代表了胃癌中显著缺失的新发现。在17号染色体短臂上，已知在大多数胃癌中p53通过突变或缺失而失活。在这些其他位点上胃癌失活的关键靶点仍有待确定。
