Prognostic role of ALK-1 and h-TERT expression in glioblastoma multiforme: correlation with ALK gene alterations
1
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Background: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the developing central and peripheral nervous systems during embryogenesis. Human telomerase reverse transcriptase (h-TERT) protein resumption is the main process of preservation of telomeres that maintains DNA integrity. The present study aims to evaluate the prognostic role of ALK-1 and h-TERT protein expression and their correlation with ALK gene alterations in glioblastoma multiforme (GBM). Methods: The current study is a retrospective study on a cohort of patients with GBM (n = 53) that attempted to detect ALK gene alterations using fluorescence in situ hybridization. ALK-1 and h-TERT proteins were evaluated using immunohistochemistry. Results: Score 3 ALK-1 expression was significantly associated with male sex, tumor multiplicity, Ki labeling index (Ki LI), and type of therapeutic modality. Score 3 h-TERT expression exhibited a significant association with Ki LI. ALK gene amplifications (ALK-A) were significantly associated with increased Ki LI and therapeutic modalities. Score 3 ALK-1 protein expression, score 3 h-TERT protein expression, and ALK-A were associated with poor overall survival (OS) and progression-free survival (PFS). Multivariate analysis for OS revealed that ALK gene alterations were an independent prognostic factor for OS and PFS. Conclusions: High protein expression of both ALK-1 and h-TERT, as well as ALK-A had a poor impact on the prognosis of GBM. Further studies are needed to establish the underlying mechanisms.
Abstract
Background: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the developing central and peripheral nervous systems during embryogenesis. Human telomerase reverse transcriptase (h-TERT) protein resumption is the main process of preservation of telomeres that maintains DNA integrity. The present study aims to evaluate the prognostic role of ALK-1 and h-TERT protein expression and their correlation with ALK gene alterations in glioblastoma multiforme (GBM). Methods: The current study is a retrospective study on a cohort of patients with GBM (n = 53) that attempted to detect ALK gene alterations using fluorescence in situ hybridization. ALK-1 and h-TERT proteins were evaluated using immunohistochemistry. Results: Score 3 ALK-1 expression was significantly associated with male sex, tumor multiplicity, Ki labeling index (Ki LI), and type of therapeutic modality. Score 3 h-TERT expression exhibited a significant association with Ki LI. ALK gene amplifications (ALK-A) were significantly associated with increased Ki LI and therapeutic modalities. Score 3 ALK-1 protein expression, score 3 h-TERT protein expression, and ALK-A were associated with poor overall survival (OS) and progression-free survival (PFS). Multivariate analysis for OS revealed that ALK gene alterations were an independent prognostic factor for OS and PFS. Conclusions: High protein expression of both ALK-1 and h-TERT, as well as ALK-A had a poor impact on the prognosis of GBM. Further studies are needed to establish the underlying mechanisms.
참고문헌 (30)
- Stoyanov GS, "Cell biology of glioblastoma multiforme : from basic science to diagnosis and treatment", Med Oncol, 35, pp.27~ (2018)
- Louis DN, "The 2016 World Health Organization classification of tumors of the central nervous system : a summary", Acta Neuropathol, 131, pp.803~820 (2016)
- Chiarle R, "The anaplastic lymphoma kinase in the pathogenesis of cancer", Nat Rev Cancer, 8, pp.11~23 (2008)
- Chiba R, "ALK signaling cascade confers multiple advantages to glioblastoma cells through neovascularization and cell proliferation", PLoS One, 12, pp.e0183516~ (2017)
- Karagkounis G, "Anaplastic lymphoma kinase expression and gene alterations in glioblastoma : correlations with clinical outcome", J Clin Pathol, 70, pp.593~599 (2017)
- Wojas-Krawczyk K, "The analysis of ALK gene rearrangement by fluorescence in situ hybridization in non-small cell lung cancer patients", Contemp Oncol(Pozn), 17, pp.484~492 (2013)
- Zito Marino F, "Unproductive effects of ALK gene amplification and copy number gain in non-small-cell lung cancer : ALK gene amplification and copy gain in NSCLC", Int J Mol Sci, 21, pp.4927~ (2020)
- Hafezi F, "The solo play of TERT promoter mutations", Cells, 9, pp.749~ (2020)
- Leao R, "Mechanisms of human telomerase reverse transcriptase(hTERT)regulation : clinical impacts in cancer", J Biomed Sci, 25, pp.22~ (2018)
- Potharaju M, "Clinicopathological analysis of HIF-1alpha and TERT on survival outcome in glioblastoma patients : a prospective, single institution study", J Cancer, 10, pp.2397~2406 (2019)
- Persson A, "Different assessments of immunohistochemically stained Ki-67 and hTERT in glioblastoma multiforme yield variable results : a study with reference to survival prognosis", Clin Neuropathol, 27, pp.224~233 (2008)
- Stupp R, "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma", N Engl J Med, 352, pp.987~996 (2005)
- Le Rhun E, "Patterns of response to crizotinib in recurrent glioblastoma according to ALK and MET molecular profile in two patients", CNS Oncol, 4, pp.381~386 (2015)
- Alidousty C, "Prevalence and potential biological role of TERT amplifications in ALK translocated adenocarcinoma of the lung", Histopathology, 78, pp.578~585 (2021)
- Saha R, "Expression of phosphatase and tensin homolog, epidermal growth factor receptor, and Ki-67 in astrocytoma : a prospective study in a tertiary care hospital", Indian J Med Paediatr Oncol, 35, pp.149~155 (2014)
- McLeer-Florin A, "Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice : a French study", J Thorac Oncol, 7, pp.348~354 (2012)
- Salido M, "Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer", J Thorac Oncol, 6, pp.21~27 (2011)
- Hudson L, "ALK and cMET expression in glioblastoma multiforme: implications for therapeutic targeting", Mol Cancer Ther, 10(11 Suppl), pp.A42~ (2011)
- Kulig K, "MET and ALK in glioblastoma multiforme (GBM): comparison of IHC and FISH", J Clin Oncol., 30(15 Suppl), pp.2021~ (2012)
- Peretti U, "ALK gene copy number gains in non-small-cell lung cancer : prognostic impact and clinico-pathological correlations", Respir Res, 17, pp.105~ (2016)
- Lee JS, "Prognostic implications of anaplastic lymphoma kinase gene aberrations in rhabdomyosarcoma;an immunohistochemical and fluorescence in situ hybridisation study", J Clin Pathol, 67, pp.33~39 (2014)
- Schoppmann SF, "Amplification but not translocation of anaplastic lymphoma kinase is a frequent event in oesophageal cancer", Eur J Cancer, 49, pp.1876~1881 (2013)
- Del Grosso F, "Inhibition of N-linked glycosylation impairs ALK phosphorylation and disrupts pro-survival signaling in neuroblastoma cell lines", BMC Cancer, 11, pp.525~ (2011)
- Masui K, "Elevated TERT expression in TERT-wildtype adult diffuse gliomas : histological evaluation with a novel TERT-specific antibody", Biomed Res Int, 2018, pp.7945845~ (2018)
- Leclerc C, "Calcium signaling orchestrates glioblastoma development : facts and conjunctures", Biochim Biophys Acta, 1863, pp.1447~1459 (2016)
- Nishi H, "Hypoxia-inducible factor 1 mediates upregulation of telomerase(hTERT)", Mol Cell Biol, 24, pp.6076~6083 (2004)
- Alkhaibary A, "Ki-67 labeling index in glioblastoma;does it really matter?", Hematol Oncol Stem Cell Ther, 12, pp.82~88 (2019)
- Tsidulko AY, "Prognostic relevance of NG2", CSPG4, CD44 and Ki-67 in patients with glioblastoma, 2017, pp.39, 1010428317724282~
- "Glioblastoma multiforme, NOS" (2020)[URL]
- Marzec M, "Oncogenic kinase NPM", ALK induces expression of HIF1alpha mRNA, 2011, pp.30, 1372~1378