Somatic Mutations in PIK3CA and Activation of AKT in Intraductal Tubulopapillary Neoplasms of the Pancreas
Somatic Mutations in PIK3CA and Activation of AKT in Intraductal Tubulopapillary Neoplasms of the Pancreas
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DOI：
10.1097/pas.0b013e31822769a0
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发表时间：
2011-12-01
影响因子：
5.6
通讯作者：
Furukawa, Toru
中科院分区：
文献类型：
--
作者：
Yamaguchi, Hiroshi;Kuboki, Yuko;Furukawa, Toru
导管内管状乳头状肿瘤是一种罕见的胰腺导管内肿瘤。肿瘤背后的分子畸变仍然未知。我们研究了PIK 3CA、PTEN、AKT 1、KRAS和BRAF中的体细胞突变。我们还研究了11例ITPN中磷酸化AKT、磷酸酶和张力蛋白同源物（PTEN）、肿瘤蛋白53（TP 53）、SMAD 4和CTNNB 1的异常表达，并将这些数据与50例导管内乳头状粘液性肿瘤（IPMN）（胰腺导管内肿瘤的另一种不同变体）的数据进行了比较。在11个ITPN中的3个中发现PIK 3CA突变，但在IPMN中未发现（P = 0.005; Fisher精确检验）。相比之下，在ITPN中没有发现KRAS突变，但在50个IPMN中的26个中发现了KRAS突变（P = 0.001; Fisher精确检验）。PIK 3CA突变与磷酸化AKT的强表达相关（P < 0.001; Mann-Whitney U检验）。此外，磷酸化AKT的表达在大多数ITPN中是明显的，但仅在少数IPMN中（P < 0.001; Mann-Whitney U检验）。TP 53、SMAD 4和CTNNB 1的异常表达在这些肿瘤之间没有统计学差异。PIK 3CA突变和磷酸化AKT的表达与ITPN患者的年龄、性别、组织浸润和预后无关。这些结果表明，磷脂酰肌醇3-激酶途径的激活可能在ITPN中起着至关重要的作用，但在IPMN中则不然。相反，KRAS突变似乎在IPMN中起主要作用，但在ITPN中不起作用。活化的磷脂酰肌醇3-激酶通路可能成为ITPN分子诊断和治疗的潜在靶点。
Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P < 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P < 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.