Clinical and Prognostic Implications of 1p/19q, IDH, BRAF, MGMT Promoter, and TERT Promoter Alterations, and Expression of Ki-67 and p53 in Human Gliomas

Abstract

Background and Objective

Genetic alterations, including IDH, BRAF, and TERT promoter mutations (IDH-mu, BRAF-mu, TERTp-mu, respectively), 1p/19q co-deletion (1p/19q-codel), and MGMT promoter methylation (MGMTp-M), are correlated with glioma tumor development. Therefore, these genetic alterations could serve as biomarkers for the diagnosis, prognosis, and classification of gliomas, combined with the immunohistochemical markers Ki-67 and p53. However, the correlation between these alterations and the expression of Ki-67 and p53 is poorly understood.

Methods

We analyzed the prevalence and prognosis of these five alterations, as well as Ki-67 and p53 expression, in 103 primary grade II–IV gliomas via fluorescence qPCR, Sanger sequencing, fluorescence in situ hybridization, and immunohistochemistry.

Results

In the 103 cases, MGMTp-M was the most common alteration (70.9%), followed by TERTp-mu (58.3%), IDH-mu (46.6%), 1p/19q-codel (34.0%), and BRAF-mu (5.8%). No cases showed quintuple-positive alterations, but 26 cases (25.2%) showed quadruple-positive alterations (IDH-mu/TERTp-mu/MGMTp-M/1p/19q-codel). The percentage of TERTp-mu and 1p/19q-codel cases decreased with p53 expression, and the percentage of IDH-mu and 1p/19q-codel cases decreased with Ki-67 expression. IDH-mu, MGMTp-M, and 1p/19q-codel were positive factors for survival rates in glioma patients, while TERTp-mu, p53, and Ki-67 positivity were negative factors. Old age, histological grade IV, IDH-mu, 1p/19q-codel, Ki-67+, and p53+/Ki-67+ were significantly correlated with overall survival (OS). However, only p53+/Ki-67+ was an independent prognostic factor for OS in the multivariate Cox-model analysis.

Conclusion

IDH-mu only and quadruple-positivity were associated with good OS in glioma patients, while TERTp-mu only, TERTp-mu/MGMTp-M and p53+/Ki-67+ were associated with poor prognosis. Combining these genomic alterations and Ki-67/p53 expression should have clinical value in gliomas.

Keywords:

• human glioma
• biomarker
• correlation analysis
• genetic alteration
• survival rate

Acknowledgments

This study was supported by two joint research projects of Southwest Medical University and Luzhou city (2017LZXNYD-J14 and 2018LZXNYD-ZK22), Natural Science Foundation of Southwest Medical University (2019ZQN070), as well as the doctoral research initiation fund of the Affiliated Hospital of Southwest Medical University (no. 16238).

Abbreviations

IDH, isocitrate dehydrogenase; TERTp, telomerase reverse transcriptase promoter; MGMTp, O6-methylguanine-DNA methyltransferase promoter; 1p/19q, chromosome arms 1p and 19q; BRAF, v-raf murine sarcoma oncogene homologue B1; Mu, mutation; Wt, wild-type; M, methylation; UM, unmethylation; 1p-del, 1p-deletion; 19q-del, 19q-deletion; Codel, codeletion; A, astrocytoma; AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; AOA, anaplastic oligoastrocytoma; O, oligodendroglioma; OA, oligoastrocytoma; GM, glioblastoma; OS, overall survival.

Author Contributions

All authors contributed to data analysis, drafting, or revising the article. All authors gave final approval of the manuscript to be published, agreed to the submitted journal, and agreed to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest in this work.