Research Papers:

Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening

Jeeyun Lee, Hee Cheol Kim, Jung Yong Hong, Kai Wang, Sun Young Kim, Jiryeon Jang, Seung Tae Kim, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Young Suk Park, Jiyun Lee, Woo Yong Lee, Yoon Ah Park, Jung Wook Huh, Seong Hyeon Yun, In-Gu Do, Seok Hyung Kim, Sohail Balasubramanian, Philip J. Stephens, Jeffrey S. Ross, Gang Gary Li, Zachary Hornby, Siraj M. Ali, Vincent A. Miller, Kyoung-Mee Kim, Sai-Hong Ignatius Ou _

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Oncotarget. 2015; 6:24320-24332. https://doi.org/10.18632/oncotarget.4462

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Jeeyun Lee1,*, Hee Cheol Kim2,*, Jung Yong Hong3,*, Kai Wang4, Sun Young Kim1, Jiryeon Jang1, Seung Tae Kim1, Joon Oh Park1, Ho Yeong Lim1, Won Ki Kang1, Young Suk Park1, Jiyun Lee1, Woo Yong Lee2, Yoon Ah Park2, Jung Wook Huh2, Seong Hyeon Yun2, In-Gu Do5, Seok Hyung Kim5, Sohail Balasubramanian4, Philip J. Stephens4, Jeffrey S. Ross4,6, Gang Gary Li7, Zachary Hornby7, Siraj M. Ali4, Vincent A. Miller4, Kyoung-Mee Kim5,8, Sai-Hong Ignatius Ou9

1Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

2Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

3Department of Internal Medicine, Chung-Ang University College of Medicine, Dongjak-Gu, Seoul, Republic of Korea

4Foundation Medicine Inc, Cambridge, Massachusetts, USA

5Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

6Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA

7Ignyta Inc, San Diego, California, USA

8Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea

9Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA

*These authors have contributed equally to this work

Correspondence to:

Sai-Hong Ignatius Ou, e-mail: Ignatius.ou@uci.edu

Kyoung-Mee Kim, e-mail: kkmkys@skku.edu

Keywords: colorectal carcinoma, anaplastic lymphoma kinase (ALK) rearrangement, immunohistochemistry, next generation sequencing

Received: April 02, 2015     Accepted: June 19, 2015     Published: July 01, 2015


Purpose: Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies.

Experimental designs: Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial.

Results: Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib.

Conclusions: ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors.

Author Information

Jeeyun Lee

Hee Cheol Kim

Jung Yong Hong

Kai Wang

Sun Young Kim

Jiryeon Jang

Seung Tae Kim

Joon Oh Park

Ho Yeong Lim

Won Ki Kang

Young Suk Park

Jiyun Lee

Woo Yong Lee

Yoon Ah Park

Jung Wook Huh

Seong Hyeon Yun

In-Gu Do

Seok Hyung Kim

Sohail Balasubramanian

Philip J. Stephens

Jeffrey S. Ross

Gang Gary Li

Zachary Hornby

Siraj M. Ali

Vincent A. Miller

Kyoung-Mee Kim

Sai-Hong Ignatius Ou
Primary Contact  _

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