J Pathol Transl Med.  2021 May;55(3):212-224. 10.4132/jptm.2021.03.15.

Prognostic role of ALK-1 and h-TERT expression in glioblastoma multiforme: correlation with ALK gene alterations

• Elsers D
• Temerik DF
• Attia AM
• Hadia A
• Hussien MT

• KMID: 2515926
• DOI: http://doi.org/10.4132/jptm.2021.03.15

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.

Keyword

ALK-1; h-TERT; gene; Glioblastoma multiforme; Prognosis

Figure

• 

  Fig. 1. Expression of anaplastic lymphoma kinase 1 (ALK-1) immunohistochemistry in tumor cells and ALK gene alterations in glioblastoma multiforme (GBM). (A) A case of GBM shows strong cytoplasmic expression of ALK-1 in tumor cells (score 3). The inset illustrates ALK gene amplification for the same case. (B) A case of GBM shows moderate cytoplasmic staining of ALK-1 in tumor cells. The inset illustrates ALK gene gain for the same case. (C) A case of GBM shows weak cytoplasmic expression of ALK-1 in tumor cells (score 1). The inset illustrates ALK gene rearrangement for the same case. (D) A case of GBM showed negative expression of ALK-1 (score 0). The inset illustrates that the ALK gene was negative for rearrangement with a normal copy number for the same case.

• 

  Fig. 2. Expression of human telomerase reverse transcriptase (TERT) immunohistochemistry in tumor cells of glioblastoma multiforme. (A) Strong nuclear expression of TERT in >50% of tumor cells (score 3). (B) Moderate nuclear staining of TERT in 5%–50% of tumor cells (score 2). (C) Weak nuclear expression of TERT in <5% of tumor cells (score 1).

• 

  Fig. 3. Overall survival (OS) for anaplastic lymphoma kinase 1 (ALK-1), human telomerase reverse transcriptase (h-TERT) immunohistochemistry (IHC) expression, and ALK gene alterations. (A) High Ki labeling index (Ki LI) is associated with poor OS. (B) ALK-1 score 3 is associated with poor OS. (C) TERT score 3 is associated with poor OS. (D) ALK gene amplification is associated with poor OS. (E) Patients treated with adjuvant radiotherapy only had poor OS compared to those who were treated with concurrent chemoradiotherapy (CCRT) or CCRT and adjuvant temozolomide (TMZ).

• 

  Fig. 4. Progression-free survival (PFS) for anaplastic lymphoma kinase 1 (ALK-1), human telomerase reverse transcriptase (h-TERT) immunohistochemistry (IHC) expression, and ALK gene alterations. (A) High Ki labeling index (Ki LI) is associated with short PFS. (B) ALK-1 score 3 is associated with poor PFS. (C) TERT score 3 is associated with poor PFS. (D) ALK gene amplification is associated with poor PFS. (E) Patients treated with adjuvant radiotherapy only had poor PFS compared to those who were treated with concurrent chemoradiotherapy (CCRT) or CCRT and adjuvant temozolomide (TMZ).

Reference

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