胰腺导管内乳头状黏液性肿瘤进展的分子生物标志物。

Molecular biomarkers for progression of intraductal papillary mucinous neoplasm of the pancreas.

作者信息

Kuboki Yuko, Shimizu Kyoko, Hatori Takashi, Yamamoto Masakazu, Shibata Noriyuki, Shiratori Keiko, Furukawa Toru

机构信息

From the *Institute for Integrated Medical Sciences, †Department of Gastroenterology, ‡Department of Gastroenterological Surgery, Institute of Gastroenterology, §Department of Pathology, and ∥Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.

出版信息

Pancreas. 2015 Mar;44(2):227-35. doi: 10.1097/MPA.0000000000000253.

DOI:10.1097/MPA.0000000000000253

PMID:25423558

Abstract

OBJECTIVES

We aimed to identify molecular biomarkers for assessing the progression of intraductal papillary mucinous neoplasm of the pancreas (IPMN).

METHODS

We retrospectively investigated molecular aberrations and their associations with clinicopathological features in 172 IPMNs.

RESULTS

GNAS and KRAS mutations were detected in 48% and 56% of IPMNs, respectively. No mutations of EGFR, PIK3CA GNAO1, GNAQ, or GNAI2 were observed. Significant associations were observed between IPMN morphological types and GNAS mutations, KRAS mutations, the expression of phosphorylated MAPK (pMAPK), AKT, and phosphorylated AKT (pAKT), nuclear accumulation of β-catenin, SMAD4 loss, and TP53 overexpression; histological grades and the expression of EGFR, pMAPK, AKT, and pAKT, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression; invasive phenotypes and KRAS mutations, the nuclear β-catenin, and SMAD4 loss; and prognosis and SMAD4 loss and TP53 overexpression. Multivariate analysis to compare prognostic impacts of multiple molecular features revealed that TP53 overexpression was an independent prognostic factor (P = 0.030; hazard ratio, 5.533).

CONCLUSIONS

These results indicate that mutations in GNAS and KRAS, the expression of EGFR and pMAPK, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression may be relevant for assessing the clinical course of IPMN, including its progression into different morphological types, invasion, and prognosis.

摘要

目的

我们旨在识别用于评估胰腺导管内乳头状黏液性肿瘤（IPMN）进展的分子生物标志物。

方法

我们回顾性研究了172例IPMN中的分子异常及其与临床病理特征的关联。

结果

分别在48%和56%的IPMN中检测到GNAS和KRAS突变。未观察到EGFR、PIK3CA、GNAO1、GNAQ或GNAI2的突变。在IPMN形态学类型与GNAS突变、KRAS突变、磷酸化MAPK（pMAPK）、AKT和磷酸化AKT（pAKT）的表达、β-连环蛋白核积聚、SMAD4缺失以及TP53过表达之间观察到显著关联；在组织学分级与EGFR、pMAPK、AKT和pAKT的表达、核β-连环蛋白、SMAD4缺失以及TP53过表达之间；在侵袭性表型与KRAS突变、核β-连环蛋白和SMAD4缺失之间；以及在预后与SMAD4缺失和TP53过表达之间。比较多种分子特征对预后影响的多变量分析显示，TP53过表达是一个独立的预后因素（P = 0.030；风险比，5.533）。