Institute for Integrated Medical Sciences, Institute of Gastroenterology, Deparment of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
Sci Rep. 2011;1:161. doi: 10.1038/srep00161. Epub 2011 Nov 18.
Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic cystic neoplasm that is often invasive and metastatic, resulting in a poor prognosis. Few molecular alterations unique to IPMN are known. We performed whole-exome sequencing for a primary IPMN tissue, which uncovered somatic mutations in KCNF1, DYNC1H1, PGCP, STAB1, PTPRM, PRPF8, RNASE3, SPHKAP, MLXIPL, VPS13C, PRCC, GNAS, KRAS, RBM10, RNF43, DOCK2, and CENPF. We further analyzed GNAS mutations in archival cases of 118 IPMNs and 32 pancreatic ductal adenocarcinomas (PDAs), which revealed that 48 (40.7%) of the 118 IPMNs but none of the 32 PDAs harbored GNAS mutations. G-protein alpha-subunit encoded by GNAS and its downstream targets, phosphorylated substrates of protein kinase A, were evidently expressed in IPMN; the latter was associated with neoplastic grade. These results indicate that GNAS mutations are common and specific for IPMN, and activation of G-protein signaling appears to play a pivotal role in IPMN.
导管内乳头状黏液性肿瘤（IPMN）是一种常见的胰腺囊性肿瘤，常具有侵袭性和转移性，预后不良。目前仅发现少数几种特定于 IPMN 的分子改变。我们对原发性 IPMN 组织进行了全外显子组测序，发现 KCNF1、DYNC1H1、PGCP、STAB1、PTPRM、PRPF8、RNASE3、SPHKAP、MLXIPL、VPS13C、PRCC、GNAS、KRAS、RBM10、RNF43、DOCK2 和 CENPF 存在体细胞突变。我们进一步分析了 118 例 IPMN 和 32 例胰腺导管腺癌（PDAC）存档病例中的 GNAS 突变，结果显示 118 例 IPMN 中有 48 例（40.7%）存在 GNAS 突变，但 32 例 PDAC 中无一例存在 GNAS 突变。GNAS 编码的 G 蛋白 α 亚基及其下游靶标，蛋白激酶 A 的磷酸化底物，在 IPMN 中明显表达；后者与肿瘤分级相关。这些结果表明 GNAS 突变在 IPMN 中常见且具有特异性，G 蛋白信号的激活似乎在 IPMN 中发挥关键作用。
