Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression
Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression
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DOI：
10.1007/s00535-011-0482-y
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发表时间：
2012-02-01
影响因子：
6.3
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
--
作者：
Mohri, Dai;Asaoka, Yoshinari;Koike, Kazuhiko
导管内乳头状粘液性肿瘤（IPMN）被认为是胰腺癌的前驱病变，胰腺癌是一种独特的病理实体。 IPMN有不同临床特征的亚型。然而，IPMN 导致癌症进展的分子机制仍然很大程度上未知。在本研究中，我们检查了 IPMN 亚型之间遗传改变的差异。通过苏木精和伊红 (H&E) 以及粘蛋白免疫染色将手术切除的 IPMN (n = 25) 分为四个亚型。检测了KRAS、BRAF和PIK3CA基因突变以及CDKN2A、TP53、SMAD4、磷酸化ERK和磷酸化SMAD1/5/8蛋白的表达。本研究中有11个胃型、11个肠型、1个胰胆型和2个嗜酸细胞型。然后我们比较了两种主要亚型：胃型和肠型 IPMN。胃型 IPMN 的 KRAS 突变发生率显着高于肠型 (3/11, 27.3%; p < 0.05) (3/11, 81.8%)，尽管肠型 IPMN 的不典型增生程度高于胃型 (p < 0.01)。所有具有 KRAS 突变的病例均显示磷酸化 ERK 免疫染色。相反，与胃型 IPMN (3/11, 27.3%; p < 0.05%) 相比，肠型 (9/11, 81.8%) 显示出更频繁的 SMAD1/5/8 磷酸化。不同亚型的 IPMN 中胰腺癌进展可能存在不同的机制。特别是，KRAS 突变和骨形态发生蛋白-SMAD 信号传导状态可能是 IPMN 患者胰腺癌的两个代表性途径的关键分歧步骤。
Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes.Surgically resected IPMNs (n = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS, BRAF, and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined.There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type (p < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p < 0.05%).There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.