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Combinational Analysis of FISH and Immunohistochemistry Reveals Rare Genomic Events in ALK Fusion Patterns in NSCLC that Responds to Crizotinib Treatment.
J Thorac Oncol 2017; 12(1):94-101JT

Abstract

INTRODUCTION

The purpose of this study was to explore the complicated rearrangement mechanisms underlying cases with atypical and negative anaplastic lymphoma receptor tyrosine kinase gene (ALK) fluorescence hybridization (FISH) and positive immunohistochemistry (IHC) results and to stress the importance of combinational assay of these two methods in current pathological diagnosis.

METHODS

A total of 3128 NSCLCs were screened for ALK fusions through both FISH analysis and IHC assays with Ventana-D5F3 antibody. Fourteen cases with atypical and negative FISH results with the current criteria and positive IHC results were analyzed with targeted next-generation sequencing (NGS).

RESULTS

Of the 3128 cases tested, 228 (7.3%) and 214 (6.8%) were ALK positive by IHC and FISH, respectively. Fourteen cases with negative and atypical FISH results all demonstrated IHC positivity. Of 2991 cases, eight (0.27%) with negative FISH results demonstrated echinoderm microtubule associated protein like 4 gene (EML4)-ALK fusions revealed by targeted NGS, and the relative abundance of fusion ranged from 0.9% to 46.8%. Three of 2991 cases (0.1%) did not exhibit any type of ALK fusions. In addition, two patients showed an isolated 5' side signal and targeted NGS revealed two novel ALK partner genes, baculoviral IAP repeat containing 6 gene (BIRC6) and phosphatidylinositol binding clathrin assembly protein gene (PICALM). One patient showed an isolated and attenuated 3' red signal and demonstrated a novel translocation partner with CCAAT/enhancer binding protein zeta gene (CEBPZ). Of all the patients, four received crizotinib treatment and demonstrated partial responses at the end of follow-up.

CONCLUSIONS

Our study showed that patients with negative and atypical ALK FISH patterns may have positive results for IHC testing and harbor the translocation partners of EML4 or other genes. Therefore, additional testing with NGS should be conducted to explore the molecular mechanisms underlying the complicated gene rearrangement events.

Authors+Show Affiliations

Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.Burning Rock Biotech, Guangzhou, People's Republic of China.Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China. Electronic address: jmying@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27614248

Citation

Li, Wenbin, et al. "Combinational Analysis of FISH and Immunohistochemistry Reveals Rare Genomic Events in ALK Fusion Patterns in NSCLC That Responds to Crizotinib Treatment." Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer, vol. 12, no. 1, 2017, pp. 94-101.
Li W, Zhang J, Guo L, et al. Combinational Analysis of FISH and Immunohistochemistry Reveals Rare Genomic Events in ALK Fusion Patterns in NSCLC that Responds to Crizotinib Treatment. J Thorac Oncol. 2017;12(1):94-101.
Li, W., Zhang, J., Guo, L., Chuai, S., Shan, L., & Ying, J. (2017). Combinational Analysis of FISH and Immunohistochemistry Reveals Rare Genomic Events in ALK Fusion Patterns in NSCLC that Responds to Crizotinib Treatment. Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer, 12(1), pp. 94-101. doi:10.1016/j.jtho.2016.08.145.
Li W, et al. Combinational Analysis of FISH and Immunohistochemistry Reveals Rare Genomic Events in ALK Fusion Patterns in NSCLC That Responds to Crizotinib Treatment. J Thorac Oncol. 2017;12(1):94-101. PubMed PMID: 27614248.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combinational Analysis of FISH and Immunohistochemistry Reveals Rare Genomic Events in ALK Fusion Patterns in NSCLC that Responds to Crizotinib Treatment. AU - Li,Wenbin, AU - Zhang,Jing, AU - Guo,Lei, AU - Chuai,Shannon, AU - Shan,Ling, AU - Ying,Jianming, Y1 - 2016/09/08/ PY - 2016/07/11/received PY - 2016/08/12/revised PY - 2016/08/24/accepted PY - 2016/9/11/pubmed PY - 2017/11/29/medline PY - 2016/9/11/entrez KW - ALK KW - Complicated rearrangement KW - Discordant cases KW - Fluorescence in situ hybridization KW - Immunohistochemistry SP - 94 EP - 101 JF - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JO - J Thorac Oncol VL - 12 IS - 1 N2 - INTRODUCTION: The purpose of this study was to explore the complicated rearrangement mechanisms underlying cases with atypical and negative anaplastic lymphoma receptor tyrosine kinase gene (ALK) fluorescence hybridization (FISH) and positive immunohistochemistry (IHC) results and to stress the importance of combinational assay of these two methods in current pathological diagnosis. METHODS: A total of 3128 NSCLCs were screened for ALK fusions through both FISH analysis and IHC assays with Ventana-D5F3 antibody. Fourteen cases with atypical and negative FISH results with the current criteria and positive IHC results were analyzed with targeted next-generation sequencing (NGS). RESULTS: Of the 3128 cases tested, 228 (7.3%) and 214 (6.8%) were ALK positive by IHC and FISH, respectively. Fourteen cases with negative and atypical FISH results all demonstrated IHC positivity. Of 2991 cases, eight (0.27%) with negative FISH results demonstrated echinoderm microtubule associated protein like 4 gene (EML4)-ALK fusions revealed by targeted NGS, and the relative abundance of fusion ranged from 0.9% to 46.8%. Three of 2991 cases (0.1%) did not exhibit any type of ALK fusions. In addition, two patients showed an isolated 5' side signal and targeted NGS revealed two novel ALK partner genes, baculoviral IAP repeat containing 6 gene (BIRC6) and phosphatidylinositol binding clathrin assembly protein gene (PICALM). One patient showed an isolated and attenuated 3' red signal and demonstrated a novel translocation partner with CCAAT/enhancer binding protein zeta gene (CEBPZ). Of all the patients, four received crizotinib treatment and demonstrated partial responses at the end of follow-up. CONCLUSIONS: Our study showed that patients with negative and atypical ALK FISH patterns may have positive results for IHC testing and harbor the translocation partners of EML4 or other genes. Therefore, additional testing with NGS should be conducted to explore the molecular mechanisms underlying the complicated gene rearrangement events. SN - 1556-1380 UR - https://www.unboundmedicine.com/medline/citation/27614248/Combinational_Analysis_of_FISH_and_Immunohistochemistry_Reveals_Rare_Genomic_Events_in_ALK_Fusion_Patterns_in_NSCLC_that_Responds_to_Crizotinib_Treatment_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1556-0864(16)30930-3 DB - PRIME DP - Unbound Medicine ER -