STK11段
Peutz-Jeghers综合征
杂合子丢失
生物
腺癌
抑癌基因
癌症研究
种系突变
考登综合征
微卫星不稳定性
发病机制
移码突变
癌症
病理
遗传学
癌变
突变
医学
等位基因
基因
微卫星
克拉斯
结直肠癌
作者
Stephen B. Gruber,Mark M. Entius,Gloria M. Petersen,Steven J. Laken,Patti A. Longo,R Boyer,Albert M. Levin,Urvi Mujumdar,Jeffrey M. Trent,Kenneth W. Kinzler,Bert Vogelstein,Stanley R. Hamilton,Mihael H. Polymeropoulos,G. J. A. Offerhaus,Francis M. Giardiello
出处
期刊:PubMed
日期:1998-12-01
卷期号:58 (23): 5267-70
被引量:59
摘要
Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.
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