Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Cancer. 2013 May 1;119(9):1669-74. doi: 10.1002/cncr.27955. Epub 2013 Jan 18.
Similar to the pancreatic intraepithelial neoplasia (PanIN)-pancreatic carcinoma sequence model, intrahepatic cholangiocarcinoma (ICC) also reportedly follows a stepwise carcinogenesis process through the a precursor lesion: biliary intraepithelial neoplasia (BilIN). For this study, the authors investigated the status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) mutations and tumor protein 53 (p53) overexpression in the stepwise process of cholangiocarcinogenesis.
Thirty patients with hepatolithiasis were surveyed, and their lesions were categorized as follows: non-neoplastic large bile duct (LBD) (n = 12), peribiliary gland (PBG) (n = 9), BilIN-1 (low-grade dysplasia; n = 12), BilIN-2 (high-grade dysplasia; n = 16), and BilIN-3 (noninvasive or in situ carcinoma; n = 10). KRAS mutation at codons 12 and 13 and GNAS mutations at codon 201 were analyzed using genomic DNA extracted from isolated lesions by laser capture microdissection [corrected]. Immunohistochemical expression of p53 also was evaluated in BilIN lesions, ICCs, and extrahepatic cholangiocarcinomas (ExCCs).
A prevalence of KRAS mutations was identified in patients with ICC (31.5%), BilIN-3 (30%), and BilIN-2 (43.8%) compared with BilIN-1 (25%). Furthermore, KRAS mutations were detected in LBD lesions (41.7%) and PBG lesions (44.4%), and these mutations were observed with greater frequency in patients who had BilIN with KRAS mutations. GNAS mutations were not identified in any of the ICCs or other lesions examined. The overexpression of p53 was not identified in BilIN lesions and was less frequent in ICCs (18.2%) compared with ExCCs (38.1%) and gallbladder carcinomas (61.5%).
KRAS mutations, which were present in approximately 33% of BilIN lesions, occurred as an early molecular event during the progression of BilIN to ICC, whereas p53 overexpression was identified as a late molecular event. Furthermore, the current results indicted that BilIN also may arise from LBD and PBG lesions in patients who have hepatolithiasis with KRAS mutations.
类似于胰腺上皮内瘤变（PanIN）-胰腺癌序列模型，肝内胆管癌（ICC）也被报道遵循逐步致癌发生过程，通过一个前体病变：胆管上皮内瘤变（BilIN）。在这项研究中，作者研究了 v-Ki-ras2 Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）和 GNAS 复合物基因座（GNAS）突变以及肿瘤蛋白 53（p53）在胆管癌发生的逐步过程中的状态。
对 30 例胆石症患者进行调查，其病变分为以下几类：非肿瘤性大胆管（LBD）（n=12）、周围腺体（PBG）（n=9）、BilIN-1（低级别异型增生；n=12）、BilIN-2（高级别异型增生；n=16）和 BilIN-3（非浸润性或原位癌；n=10）。通过激光捕获显微切割[校正]从分离病变中提取的基因组 DNA 分析 KRAS 密码子 12 和 13 点突变和 GNAS 密码子 201 点突变。还评估了 p53 在 BilIN 病变、ICC 和肝外胆管癌（ExCC）中的免疫组化表达。
ICC（31.5%）、BilIN-3（30%）和 BilIN-2（43.8%）患者的 KRAS 突变发生率高于 BilIN-1（25%）。此外，KRAS 突变发生在 LBD 病变（41.7%）和 PBG 病变（44.4%）中，并且在具有 KRAS 突变的 BilIN 患者中观察到这些突变的频率更高。在检查的 ICC 或其他病变中均未发现 GNAS 突变。p53 的过表达在 BilIN 病变中未被发现，在 ICC（18.2%）中比 ExCC（38.1%）和胆囊癌（61.5%）中少见。
在大约 33%的 BilIN 病变中存在 KRAS 突变，这是 BilIN 向 ICC 进展过程中的早期分子事件，而 p53 过表达则是晚期分子事件。此外，目前的结果表明，在有 KRAS 突变的胆石症患者中，BilIN 也可能来源于 LBD 和 PBG 病变。
