Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening
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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
Sai-Hong Ignatius Ou, e-mail: Ignatius.email@example.com
Kyoung-Mee Kim, e-mail: firstname.lastname@example.org
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.
Hee Cheol Kim
Jung Yong Hong
Sun Young Kim
Seung Tae Kim
Joon Oh Park
Ho Yeong Lim
Won Ki Kang
Young Suk Park
Woo Yong Lee
Yoon Ah Park
Jung Wook Huh
Seong Hyeon Yun
Seok Hyung Kim
Philip J. Stephens
Jeffrey S. Ross
Gang Gary Li
Siraj M. Ali
Vincent A. Miller
Sai-Hong Ignatius Ou
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