The absence of a novel intron 19-retaining ALK transcript (ALK-I19) and MYCN amplification correlates with an excellent clinical outcome in neuroblastoma patients
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Abdulraheem Alshareef1,2, Meredith S. Irwin3, Nidhi Gupta2, Hai-Feng Zhang2,4, Moinul Haque2, Scott D. Findlay5,6, Bo Kyung Alex Seong7, Justine Lai2, Mohammed Rayis8, Sadeq Al-Dandan9 and Raymond Lai2,5,10
1Department of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia
2Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
3Division of Haematology-Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada
4Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
5Department of Oncology, University of Alberta, Edmonton, Canada
6Department of Anatomy and Cell Biology, Faculty of Medicine and Dentistry, University of Western Ontario, London, Canada
7Department of Medical Biophysics, University of Toronto, Toronto, Canada
8Department of Pediatric Oncology, King Fahad Medical City, Riyadh, Saudi Arabia
9Department of Anatomical Pathology, King Fahad Medical City, King Saud bin Abdulaziz University, Riyadh, Saudi Arabia
10DynaLIFE Medical Laboratories, Edmonton, Canada
Raymond Lai, email: [email protected]
Keywords: neuroblastoma; anaplastic lymphoma kinase; alk-expressing human cancers; intron-retention transcript; prognostic markers
Received: January 04, 2017 Accepted: December 28, 2017 Published: January 12, 2018
ALK missense mutations are detected in 8% of neuroblastoma (NB) tumors at diagnosis and confer gain-of-function oncogenic effects. The mechanisms by which the expression of wild-type or mutant ALK, which is detectable in the majority of cases, is regulated are not well understood. We have identified a novel ALK transcript characterized by the retention of intron 19 (ALK-I19). ALK-I19 was detected in 4/4 NB cell lines, but not other non-NB cells with ALK aberrations. The functional significance of ALK-I19 was determined by specific siRNA knockdown of this transcript, which resulted in substantially decreased expression of the fully-spliced ALK transcripts (FS-ALK) and a significant reduction in cell growth. We also demonstrate that ALK-I19 is a precursor of FS-ALK. ALK-I19 was detected in 14/37 (38%) tumors from patients with newly diagnosed NB. ALK-I19 expression correlated with undifferentiated histology and strong ALK protein expression detectable by immunohistochemistry. Importantly, patients with tumors that did not express ALK-I19 and lacked MYCN amplification had an excellent clinical outcome, with 19/19 patients survived at 5-years. In conclusion, ALK-I19 is a novel ALK transcript that likely represents a marker of undifferentiated NB cells. The absence of ALK-I19 and MYCN amplification is a useful prognostic marker for NB patients.
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