KIF5B-ALK, a Novel Fusion Oncokinase Identified by an Immunohistochemistry-based Diagnostic System for ALK-positive Lung Cancer

被引：568

作者：

Takeuchi, Kengo ^{[1
]}

Choi, Young Lim ^{[3
]}

Togashi, Yuki ^{[1
]}

Soda, Manabu ^{[3
]}

Hatano, Satoko ^{[1
]}

Inamura, Kentaro ^{[1
]}

Takada, Shuji ^{[3
]}

Ueno, Toshihide ^{[3
]}

Yamashita, Yoshihiro ^{[3
]}

Satoh, Yukitoshi ^{[2
]}

Okumura, Sakae ^{[2
]}

Nakagawa, Ken ^{[2
]}

Ishikawa, Yuichi ^{[1
]}

Mano, Hiroyuki ^{[3
,4
]}

机构：

[1] Japanese Fdn Canc Res, Inst Canc, Div Pathol, Tokyo 1358550, Japan

[2] Canc Inst Hosp, Dept Thorac Surg Oncol, Thorac Ctr, Japanese Fdn Canc Res, Tokyo, Japan

[3] Jichi Med Univ, Div Funct Genom, Mibu, Tochigi, Japan

[4] Japan Sci & Technol Agcy, CREST, Saitama, Japan

来源：

CLINICAL CANCER RESEARCH | 2009年 / 15卷 / 09期

基金：

日本学术振兴会;

关键词：

ANAPLASTIC LYMPHOMA KINASE; EML4-ALK FUSION; GENE FUSIONS; CHROMOSOME; INHIBITORS; PROTEINS; PCR;

D O I：

10.1158/1078-0432.CCR-08-3248

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: EML4-ALK is a transforming fusion tyrosine kinase, several isoforms of which have been identified in lung cancer. Immunohistochemical detection of EML4-ALK has proved difficult, however, likely as a result of low transcriptional activity conferred by the promoter-enhancer region of EML4. The sensitivity of EML4-ALK detection by immunohistochemistry should be increased adequately. Experimental Design: We developed an intercalated antibody-enhanced polymer (iAEP) method that incorporates an intercalating antibody between the primary antibody to ALK and the dextran polymer-based detection reagents. Results: Our iAEP method discriminated between tumors positive or negative for EML4-ALK in a test set of specimens. Four tumors were also found to be positive for ALK in an archive of lung adenocarcinoma (n = 130) and another 4 among fresh cases analyzed in a diagnostic laboratory. These 8 tumors were found to include 1 with EML4-ALK variant 1, 1 with variant 2, 3 with variant 3, and 2 with previously unidentified variants (designated variants 6 and 7). Inverse reverse transcription-PCR analysis revealed that the remaining tumor harbored a novel fusion in which intron 24 of KIF5B was ligated to intron 19 of ALK. Multiplex reverse transcription-PCR analysis of additional archival tumor specimens identified another case of lung adenocarcinoma positive for KIF5B-ALK. Conclusions: The iAEP method should prove suitable for immunohistochemical screening of tumors positive for ALK or ALK fusion proteins among pathologic archives. Coupling of PCR-based detection to the iAEP method should further facilitate the rapid identification of novel ALK fusion genes such as KIF5B-ALK.

引用

页码：3143 / 3149

页数：7

共 22 条

[21] A mouse model for EML4-ALK-positive lung cancer [J].

Soda, Manabu ;

Takada, Shuji ;

Takeuchi, Kengo ;

Choi, Young Lim ;

Enomoto, Munehiro ;

Ueno, Toshihide ;

Haruta, Hidenori ;

Hamada, Toru ;

Yamashita, Yoshihiro ;

Ishikawa, Yuichi ;

Sugiyama, Yukihiko ;

Mano, Hiroyuki .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (50) :19893-19897

[22] Multiplex Reverse Transcription-PCR Screening for EML4-ALK Fusion Transcripts [J].

Takeuchi, Kengo ;

Choi, Young Lim ;

Soda, Manabu ;

Inamura, Kentaro ;

Togashi, Yuki ;

Hatano, Satoko ;

Enomoto, Munehiro ;

Takada, Shuji ;

Yamashita, Yoshihiro ;

Satoh, Yukitoshi ;

Okumura, Sakae ;

Nakagawa, Ken ;

Ishikawa, Yuichi ;

Mano, Hiroyuki .

CLINICAL CANCER RESEARCH, 2008, 14 (20) :6618-6624

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