High ALK expression was correlated with advanced stage and poor outcome in neuroblastoma

High ALK expression was correlated with advanced stage and poor outcome in neuroblastoma

High ALK expression was correlated with advanced stage and poor outcome in neuroblastoma

(구연):
Release Date : 2014. 10. 25(토)
Ji Won Lee1, Sung-Hye Park2, Che Ry Hong1, Hee Young Ju1, Hyery Kim1, Hyoung Jin Kang1, Kyung Duk Park1, Hee Young Shin1 , Hyo Seop Ahn1
Seoul National University College of Medicine Department of Pediatrics1
Seoul Cancer Research Institute2
이지원1, 박성혜2, 홍채리1, 주희영1, 김혜리1, 강형진1, 박경덕1, 신희영1 , 안효섭1
서울대학교 의과대학 소아과학교실1
서울대학교 의과대학 병리학교실2

Abstract

b>Introduction:/b> Neuroblastoma is a childhood malignancy which showed heterogeneous clinical course. In this study, MYCN amplification, anaplastic lymphoma kinase (ALK) mutation and amplification, ALK expression, loss of the nuclear ATRX protein, and TERT expression were studied to investigate if there are any correlations between these molecular characteristics and clinical features or outcomes. b>Materials and methods:/b> Among the patients diagnosed with neuroblastoma and treated at Seoul National University Children’s Hospital between January 2002 to July 2012, 72 patients whose initial tumor samples were evaluable were enrolled in this study. Mutation analysis of the ALK gene was performed with PCR and direct sequencing. Immunohistochemical staining was performed on tissue microarray sections using an ALK monoclonal antibody, a polyclonal antibody against ATRX and a monoclonal anti-TERT antibody. Fluorescence in situ hybridization was performed to investigate MYCN and ALK amplification. b>Results:/b> Seven (10.0%) patients had MYCN amplification at initial diagnosis, and relapse rate was significantly higher in patients with MYCN amplification compared to the other patients (77.8% vs 19.4%, P=0.000). Forty (55.6%) patients showed high ALK expression, and high ALK expression was observed more frequently in stage 3-4 neuroblastoma ( P=0.001). Relapse rate was significantly higher in patients with high ALK expression compared to the other patients (47.5% vs 11.3%, P=0.007). ALK mutation was found only in 2 patients, and ALK amplification was not found in any of the patients. Nine (13.0%) patients showed loss of nuclear ATRX protein expression. Interestingly, loss of ATRX protein was found not only in older patients with stage IV but also in younger patients with stage I-III neuroblastoma. Strong TERT positivity was associated with advance stage, but TERT expression was not correlated with treatment outcomes. b>Conclusion:/b> Although only small population of patients had ALK mutation and amplification, ALK expression was found in larger group of patients, and high ALK expression was correlated with advanced stage and poor outcome in neuroblastoma. With this result, ALK targeted therapy could be considered as a valid therapeutic strategy for refractory neuroblastoma having high ALK expression irrespective of genetic ALK status.

Keywords: neuroblastoma, anaplastic lymphoma kinase,