Clinical Significance of the Genetic Landscape of Pancreatic Cancer and Implications for Identification of Potential Longterm Survivors

被引：221

作者：

Yachida, Shinichi ^{[1
,5
]}

White, Catherine M. ^{[1
]}

Naito, Yoshiki ^{[1
,6
]}

Zhong, Yi ^{[1
]}

Brosnan, Jacqueline A. ^{[1
]}

Macgregor-Das, Anne M. ^{[1
]}

Morgan, Richard A. ^{[1
]}

Saunders, Tyler ^{[1
]}

Laheru, Daniel A. ^{[2
]}

Herman, Joseph M. ^{[4
]}

Hruban, Ralph H. ^{[1
]}

Klein, Alison P. ^{[2
]}

Jones, Sian ^{[2
]}

Velculescu, Victor ^{[7
]}

Wolfgang, Christopher L. ^{[1
,3
]}

Iacobuzio-Donahue, Christine A. ^{[1
,2
,3
]}

机构：

[1] Johns Hopkins Univ Hosp, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA

[2] Johns Hopkins Med Inst, Dept Oncol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[3] Johns Hopkins Med Inst, Dept Surg, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[4] Johns Hopkins Med Inst, Dept Radiat Oncol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[5] Natl Canc Ctr, Res Inst, Tokyo 104, Japan

[6] Kurume Univ, Sch Med, Kurume, Fukuoka 830, Japan

[7] Johns Hopkins Med Inst, Lugwig Ctr Canc Genet & Therapeut, Baltimore, MD 21205 USA

来源：

CLINICAL CANCER RESEARCH | 2012年 / 18卷 / 22期

基金：

美国国家卫生研究院;

关键词：

DUCTAL ADENOCARCINOMA; PROGNOSTIC MARKERS; P53; GENE; MUTATIONS; INACTIVATION; METASTASIS; CARCINOMA; TUMORS; SMAD4; KRAS;

D O I：

10.1158/1078-0432.CCR-12-1215

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Purpose: Genetic alterations of KRAS, CDKN2A, TP53, and SMAD4 are the most frequent events in pancreatic cancer. We determined the extent to which these 4 alterations are coexistent in the same carcinoma, and their impact on patient outcome. Experimental Design: Pancreatic cancer patients who underwent an autopsy were studied (n = 79). Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A, and TP53 and immunolabeled for CDKN2A, TP53, and SMAD4 protein products. The number of altered driver genes in each carcinoma was correlated to clinicopathologic features. Kaplan-Meier estimates were used to determine median disease free and overall survival, and a Cox proportional hazards model used to compare risk factors. Results: The number of genetically altered driver genes in a carcinoma was variable, with only 29 patients (37%) having an alteration in all 4 genes analyzed. The number of altered driver genes was significantly correlated with disease free survival (P = 0.008), overall survival (P = 0.041), and metastatic burden at autopsy (P = 0.002). On multivariate analysis, the number of driver gene alterations in a pancreatic carcinoma remained independently associated with overall survival (P = 0.046). Carcinomas with only 1 to 2 driver alterations were enriched for those patients with the longest survival (median 23 months, range 1 to 53). Conclusions: Determinations of the status of the 4 major driver genes in pancreatic cancer, and specifically the extent to which they are coexistent in an individual patients cancer, provides distinct information regarding disease progression and survival that is independent of clinical stage and treatment status. Clin Cancer Res; 18(22); 6339-47. (C) 2012 AACR.

引用

页码：6339 / 6347

页数：9

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