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Germline ALK variations are associated with a poor prognosis in glioma and IDH-wildtype glioblastoma

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Background

Glioma is the most common primary brain tumor. Clear classification is crucial for accurate diagnosis and individualized treatment. Histopathological characteristics and genetic alterations have shown to be related to prognosis and treatment response. Germline variants are important components of genetic alterations. However, the distribution of germline variations in glioma patients and their association with survival remain unknown.

Methods

We carried out whole-exome sequencing on 99 cases to explore germline variants in glioma. We also analyzed the association of germline variants with clinicopathological features and other prognostic indicators.

Results

All the glioma cases harbored rare germline variants. Germline ALK variants (gALK-Mut) were identified in 12/99 (12.12%) patients. The gALK-Mut patients had significantly shorter overall survival than germline ALK wildtype (gALK-WT) patients in the all glioma group (99 cases) and the subset of patients with IDH-wildtype glioblastoma (IDH-WT-GBM, 39 cases) (P = 0.013 and 0.027, respectively). The gALK-Mut patients also had higher frequency of BIRC5, PIK3CA and RPN1 somatic mutations than the gALK-WT patients in IDH-WT-GBM. Other confounding factors appeared to contribute to patient survival. The subgroup of patients in IDH-WT-GBM with gALK-Mut/TP53-Mut had worse prognosis than the gALK-WT/TP53-Mut subgroup (P = 0.031); The gALK-Mut/TERT-WT and gALK-Mut/TERT-Mut subgroups both had a worse prognosis than the gALK-WT/TERT-Mut subgroup (P = 0.031 and 0.018, respectively).

Conclusions

Our study revealed ALK variation was an independent indicator of poor prognosis in glioma and IDH-WT-GBM. It could be a promising biomarker and tractable therapeutic target for this deadly disease.

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Data Availability

Data are available by contacting the corresponding author.

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Funding

The author(s) received no specific funding for this work.

Author information

Author notes

  1. Linghao Bu, N. U. Farrukh Hameed have contributed equally to this research.

Authors and Affiliations

  1. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

    Linghao Bu, N. U. Farrukh Hameed, Chen Luo, Pengjie Hong & Shuai Wu

  2. Neurosurgical Institute of Fudan University, Shanghai, China

    Linghao Bu, N. U. Farrukh Hameed, Chen Luo, Pengjie Hong & Shuai Wu

  3. Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China

    Linghao Bu, N. U. Farrukh Hameed, Chen Luo, Pengjie Hong & Shuai Wu

  4. Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China

    Linghao Bu, N. U. Farrukh Hameed, Chen Luo, Pengjie Hong & Shuai Wu

  5. GenomiCare Biotechnology (Shanghai) Co. Ltd.,, Shanghai, China

    Xiaoyu Zhou & Shengzhou Wang

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by LB, NUF H and CL. The first draft of the manuscript was written by LB and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shuai Wu.

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The authors declare no conflicts of interest.

Ethical approval

The study protocol was approved by the Ethics Committee of Huashan hospital.

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All patients provided written informed consent.

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Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 Supplementary Table 1. Clinicopathological characteristics of all 99 glioma patients (XLSX 38 KB)

Supplementary file2 Supplementary Table 2. All rare germline variants in 99 glioma patients (XLSX 10 KB)

11060_2020_3676_MOESM3_ESM.xlsx

Supplementary file4 Supplementary Table 3. The damage scores of ALK variants were evaluated using PolyPhen-v2 database (XLSX 10 KB)

11060_2020_3676_MOESM4_ESM.pdf

Supplementary file3 Supplementary Figure 1. The expression of ALK between gALK-Mut and gALK-WT patient’s samples. Protein level were measured in 43 patients with glioma, 5 patients with ALK variants and 38 gALK-WT patients as normal control. The scores were calculated based on the percentage of ALK positive cells, 0%-20% positive cells were presented score 0 (A-C); 21%–50% positive cells were presented score 1 (D-F); 51%-80% positive cells were presented score 2 (G-I), as well as 81%-100% positive cells were presented score 3 (J-L). Statistical analysis showed that no significant differences were observed between two groups respectively (M-N) (PDF 162 KB)

11060_2020_3676_MOESM5_ESM.tif

Supplementary file5 Supplementary Figure 2. Summary of two major germline mutated genes identified in 39 IDH-WT-GBM cases. (A) PIK3CA. (B) BIRC5. Each circle with a stem represents a unique somatic variant. The upper labels represent gALK-Mut patients and the lower labels represent gALK-WT patients (TIF 17736 KB)

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Bu, L., Hameed, N.U.F., Luo, C. et al. Germline ALK variations are associated with a poor prognosis in glioma and IDH-wildtype glioblastoma. J Neurooncol 152, 27–36 (2021). https://doi.org/10.1007/s11060-020-03676-5

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  • DOI: https://doi.org/10.1007/s11060-020-03676-5

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