Kojima Yohei, Ohtsuka Kouki, Ohnishi Hiroaki, Abe Nobutsugu, Furuse Junji, Watanabe Takashi, Sugiyama Masanori
Department of Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
Department of Laboratory Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
Surg Today. 2018 Aug;48(8):765-772. doi: 10.1007/s00595-018-1649-4. Epub 2018 Mar 10.
Duodenal adenoma and adenocarcinoma (AC) are rare tumors, and few studies have examined their genetic features. We aimed to determine the key genetic changes in duodenal adenoma and AC, and to clarify the possible involvement of the adenoma-carcinoma sequence in duodenal tumor carcinogenesis.
Nineteen duodenal tumors collected by endoscopic mucosal resection or surgical resection were classified as AC, adenoma with high-grade dysplasia (HGD), or adenoma with low-grade dysplasia (LGD) per the World Health Organization tumor classification. When a tumor contained two or more components with different dysplasia grades, the highest grade was assigned as the tumor grade. Representative areas of these components with different grades were microdissected and evaluated by a genomic analysis. Mutational hotspots involving 50 oncogenes and tumor suppressor genes were analyzed by next-generation sequencing, and their association with the dysplasia grade was investigated.
We analyzed 27 tumor components of AC or adenoma, with 11 normal mucosal samples obtained from 19 patients with duodenal tumors. The most prevalent abnormality among 50 genes tested was the KRAS mutation, which was detected in 12/19 (63.2%) patients, followed by APC and TP53 mutations (47.4 and 36.8%, respectively). According to the tumor dysplasia grading of each component, KRAS mutations were found in 5/8 (62.5%) tumors with AC components, 6/9 (66.7%) tumors with HGD components, and 3/10 (30.0%) tumors with LGD components. TP53 mutations were found in 4/8 (50.0%) tumors with AC components, 3/9 (33.3%) tumors with HGD components, and 1/10 (10.0%) tumors with LGD components. APC mutations were found in 2/8 (25.0%) tumors with AC components, 6/9 (66.7%) tumors with HGD components, and 5/10 (50.0%) tumors with LGD components. Notably, an APC:T1556fs mutation was detected in six cases (31.6%), five of which were adenoma cases. Furthermore, STK11 mutations were confirmed in 2/8 (25.0%) AC cases and in 1/11 (9.1%) adenoma cases.
APC:T1556fs and STK11 mutations found in duodenal adenomas/ACs highlight the importance of proteins encoded by these genes in tumor development. APC mutations were identified in duodenal adenomas more frequently than in duodenal ACs, which differed from the observations of typical adenoma-carcinoma sequences seen in colorectal cancer, suggesting the limited involvement of this mechanism in duodenal cancer development.
十二指肠腺瘤和腺癌（AC）是罕见肿瘤，很少有研究检测其基因特征。我们旨在确定十二指肠腺瘤和AC中的关键基因变化，并阐明腺瘤-癌序列在十二指肠肿瘤发生过程中可能的作用。
通过内镜黏膜切除术或手术切除术收集的19例十二指肠肿瘤，根据世界卫生组织肿瘤分类标准分为AC、高级别异型增生腺瘤（HGD）或低级别异型增生腺瘤（LGD）。当肿瘤包含两个或更多具有不同异型增生级别的成分时，将最高级别指定为肿瘤级别。对这些不同级别成分的代表性区域进行显微切割，并通过基因组分析进行评估。通过二代测序分析涉及50个癌基因和肿瘤抑制基因的突变热点，并研究它们与异型增生级别的相关性。
我们分析了27个AC或腺瘤的肿瘤成分，以及从19例十二指肠肿瘤患者中获取的11个正常黏膜样本。在所检测的50个基因中，最常见的异常是KRAS突变，在12/19（63.2%）的患者中检测到，其次是APC和TP53突变（分别为47.4%和36.8%）。根据每个成分的肿瘤异型增生分级，在具有AC成分的5/8（62.5%）肿瘤、具有HGD成分的6/9（66.7%）肿瘤和具有LGD成分的3/10（30.0%）肿瘤中发现了KRAS突变。在具有AC成分的4/8（50.0%）肿瘤、具有HGD成分的3/9（33.3%）肿瘤和具有LGD成分的1/10（10.0%）肿瘤中发现了TP53突变。在具有AC成分的2/8（25.0%）肿瘤、具有HGD成分的6/9（66.7%）肿瘤和具有LGD成分的5/10（50.0%）肿瘤中发现了APC突变。值得注意的是，在6例（31.6%）中检测到APC:T1556fs突变，其中5例为腺瘤病例。此外，在2/8（25.0%）的AC病例和1/11（9.1%）的腺瘤病例中证实了STK11突变。
在十二指肠腺瘤/AC中发现的APC:T1556fs和STK11突变突出了这些基因编码的蛋白质在肿瘤发展中的重要性。在十二指肠腺瘤中发现APC突变的频率高于十二指肠AC，这与在结直肠癌中观察到的典型腺瘤-癌序列不同，表明该机制在十二指肠癌发展中的作用有限。
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