Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome.
Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome.
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发表时间：
1998-12
期刊：
影响因子：
11.2
通讯作者：
S. Gruber;Mark M. Entius;G. Petersen;S. Laken;P. Longo;R. Boyer;A. Levin;U. Mujumdar;J. Trent;K. Kinzler;B. Vogelstein;S. Hamilton;M. Polymeropoulos;G. Offerhaus;F. Giardiello
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作者：
S. Gruber;Mark M. Entius;G. Petersen;S. Laken;P. Longo;R. Boyer;A. Levin;U. Mujumdar;J. Trent;K. Kinzler;B. Vogelstein;S. Hamilton;M. Polymeropoulos;G. Offerhaus;F. Giardiello
Peutz-Jeghers综合征（PJS）是一种常染色体显性遗传病，以肠错构瘤息肉、皮肤粘膜黑色素沉积和癌症风险增加为特征。我们研究了来自约翰霍普金斯息肉病登记处的PJS家族，以确定该综合征的分子基础，并表征PJS患者胃肠道错构瘤和腺癌的发病机制。对Jeghers最早于1949年描述的家族和其他五个家族的连锁分析证实了与最近发现的PJS基因附近的19p13.3的连锁。通过基因组DNA测序，在所有6个家族中鉴定出该基因STK11的种系突变。对PJS患者的错构瘤和腺癌的分析发现，70%的肿瘤中STK11附近19p标记物的杂合性缺失（LOH）。单倍型分析表明，保留的等位基因携带一种系突变，证实STK11是一种肿瘤抑制基因。17p和18q的缺失在腺癌中被发现，但在错构瘤中未被发现，这意味着这两个区域的等位基因缺失与PJS癌症发病的晚期分子事件相对应。免疫组化显示17p LOH的腺癌也显示p53改变。18例PJS肿瘤均未出现微卫星不稳定性，APC附近5q上的LOH， K-ras原癌基因的12或13密码子突变。这些数据证明STK11是一种肿瘤抑制基因，在PJS错构瘤的发展中起着早期看门人的作用，并提示错构瘤可能是腺癌的发病前体。其他体细胞突变事件是错构瘤向腺癌发展的基础，其中一些体细胞突变在大多数结直肠癌的肿瘤进展后期是常见的。
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.