Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas
Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas
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DOI：
10.1038/modpathol.3800952
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发表时间：
2007-12-01
期刊：
影响因子：
7.5
通讯作者：
Jeuken, Judith W. M.
中科院分区：
文献类型：
--
作者：
Berkhout, Marloes;Nagtegaal, Iris D.;Jeuken, Judith W. M.
原发性小肠癌是罕见的，其发病机制知之甚少。家族性腺瘤性息肉病（FAP）患者发生十二指肠癌的风险很高。本研究的目的是为了更深入地了解十二指肠癌的发展。因此，五个FAP相关的十二指肠癌的特点是染色体和甲基化的改变，这是比较在散发性十二指肠癌中观察到的。比较基因组杂交（CGH）和甲基化特异性多重连接依赖探针扩增（MS-MLPA）进行了10个原发性散发性和5个原发性FAP相关的十二指肠癌。在FAP相关癌中，在染色体8、17和19上观察到频繁的增益，而在散发性癌中，它们发生在染色体8、12、13和20上。在60%的散发性癌中，观察到12号染色体区域的增益，这在FAP相关癌中是不存在的（P=0.04）。在免疫球蛋白超家族基因成员4（IGSF 4）、TIMP金属肽酶抑制剂3（TIMP 3）、雌激素受体1（ESR 1）、结肠腺瘤性息肉病（APC）、H-钙粘蛋白（CDH 13）和配对盒基因6（PAX 6）基因中观察到高甲基化。PAX 6的高甲基化仅在FAP相关癌中观察到（3/5），而在散发癌中未观察到（P=0.02）。总之，与散发性十二指肠癌相比，在FAP患者的十二指肠癌中未观察到12号染色体的增加。对12号染色体上这些区域的基因进行鉴定，可以更好地了解导致散发性和FAP相关的十二指肠癌的致癌途径。此外，高甲基化似乎是FAP相关的十二指肠癌以及散发性十二指肠癌的一般特征，除了PAX 6基因，其仅在FAP相关的癌中甲基化。
Primary carcinomas of the small intestine are rare and the mechanism of their pathogenesis is poorly understood. Patients with familial adenomatous polyposis (FAP) have a high risk of developing duodenal carcinomas. The aim of this study is to gain more insight into the development of duodenal carcinomas. Therefore, five FAP-related duodenal carcinomas were characterized for chromosomal and methylation alterations, which were compared to those observed in sporadic duodenal carcinomas. Comparative genomic hybridization (CGH) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed in 10 primary sporadic and five primary FAP-related duodenal carcinomas. In the FAP-related carcinomas, frequent gains were observed on chromosomes 8, 17 and 19, whereas in sporadic carcinomas they occurred on chromosomes 8, 12, 13 and 20. In 60% of the sporadic carcinomas, gains in the regions of chromosome 12 were observed which were absent in the FAP-related carcinomas (P=0.04). Hypermethylation was observed in the immunoglobulin superfamily genes member 4 (IGSF4), TIMP metallopeptidase inhibitor 3 (TIMP3), Estrogen receptor 1 (ESR1), adenomatous polyposis coli (APC), H-cadherin (CDH13) and paired box gene 6 (PAX6) genes. Hypermethylation of PAX6 was only observed in FAP-related carcinomas (3/5) and not in sporadic carcinomas (P=0.02). In conclusion, in contrast to sporadic duodenal carcinomas, gains on chromosome 12 were not observed in duodenal carcinomas of patients with FAP. Identification of the genes in these regions of chromosome 12 could lead to a better understanding of the carcinogenesis pathways leading to sporadic and FAP-related duodenal carcinomas. Furthermore, hypermethylation seems to be a general feature of both FAP-related duodenal carcinomas as well as sporadic duodenal carcinomas with the exception of the PAX6 gene, which is methylated only in FAP-related carcinomas.