The Overall Survival Rate Prognosis in Diffuse Astrocytic Patients Based on Isocitrate Dehydrogenase-1 Mutation Status (IDH1 R132H): An Indonesian Multicenter Study

doi:10.21203/rs.3.rs-3629879/v1

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The Overall Survival Rate Prognosis in Diffuse Astrocytic Patients Based on Isocitrate Dehydrogenase-1 Mutation Status (IDH1 R132H): An Indonesian Multicenter Study

https://doi.org/10.21203/rs.3.rs-3629879/v1

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Objective: The IDH1 mutation status is one of the main factors indicated the prognosis of patients with astrocytic malignancies; yet, targeted sequencing is not readily available in countries with limited resources. We aimed to analyze the association between examination IDH1 status and the overall survival rates of diffuse astrocytic tumor patients.

Methods: This retrospective cohort multicenter study included 327 diffuse astrocytic tumor patients, January 2017 – December 2022. The immunohistochemistry or PCR data of IDH1 mutation and MGMT status, WHO classification, and Karnofsky performance score (KPS) were collected. Statistical analysis was then performed to analyze their association with the median of follow-up time of 18-months.

Result: At 36-month follow-up, the overall survival rate of patients with WHO grade IV (29.23%) was significantly lower than patients with WHO grade III and II (72.24% and 82.46%; p < 0.0001). The diffuse astrocytic tumor patients’ survival rate was also significantly influenced by the KPS score (HR 1.64 [1.08 – 2.50]; p = 0.0208). The survival rate of patients with IDH1 wildtype was significantly lower than that of patients with IDH1 mutant (HR 2.13 [1.51 – 3.00]; p = 0.0004). The overall survival rate of patients with IDH1 wildtype and wildtype MGMT unmethylated was significantly lower than patients with IDH1 mutant MGMT methylated (p < 0.0001).

Conclusion: Examination of IDH1-R132H mutant is a reliable examination to predict the survival prognosis in patients with IDH1 mutant vs IDH1 wildtype; this examination could be used as an alternative to the recommended targeted sequencing of IDH1.

Prognosis

Isocitrate Dehydrogenase-1

Mutation Status

Diffuse Astrocytic Patients

Indonesian Multicenter Study

The WHO 2021 classification of adult glioma-graded tumors based on the growth pattern, behavior, and their Isocitrate dehydrogenase-1 (IDH1) mutation status, including mutant (Mut) or wildtype (WT). This classification presents new challenges related to the type of inspection and reporting of the tumor based on the results from microscopic and molecular examinations related to the genetic basis of the tumor itself.^1–3

IDH enzymes are essential in the Krebs cycle and cellular homeostasis. These enzymes convert isocitrate to alpha-ketoglutarate and NADPH, which usually protects cells against oxidative stress. Mutations in the IDH cause the failure of gene functions, which subsequently increase D-2-hydroxyglutarate, contributing to the pathogenesis of glioma.⁴ IDH mutations are seen in more than 80% of World Health Organization (WHO) grade II/III glioma patients.⁵

Numerous high-quality neuro-oncology publications have described the genetic changes and clinical behavior of IDH-Mut and IDH-WT diffuse astrocytic gliomas.^6–8 An IDH-WT diffuses, or anaplastic astrocytoma in adults with radiographic and histologic hallmarks of WHO grade II or III tumors (lack of microvascular proliferation or necrosis) behave clinically aggressively and have overall survival comparable to IDH-wild type glioblastoma (GBM), WHO grade IV.^8,9

The arginine residue required for isocitrate recognition, such as R132 for IDH1, is frequently mutated in IDH mutations linked to malignancy. In the IDH1 gene, missense mutations cause a substitution at position 132. Anti-mIDH1R132H staining gave specific results changing from arginine to histidine.^9,10 Molecular diagnosis using immunohistochemistry staining is determined as a standard test for reporting glioma cases. This study aimed to analyze the relation between immunohistochemical staining of IDH1-R132H mutant to overall survival rate of diffuse astrocytic tumor patients.

Subjects

This is a retrospective cohort multicentre study. The study received ethical approval by the Ethic Commission of Faculty of Medicine, Universitas Padjadjaran. The study was done from January 2017 – December 2022 at Dr. Hasan Sadikin Hospital, Bandung; Dharmais National Cancer Hospital, Jakarta; Siloam Hospital, Lippo Village, Karawaci; Dr. Kariadi Hospital, Semarang and Dr. Sardjito Hospital, Yogyakarta. The subjects were patients diagnosed with gliomas with WHO grades II, III, and IV those were operated at the Department of Neurosurgery each centre. Patients with severe extracranial comorbidities, damaged samples, and incomplete medical records were excluded from the study. We collected survival data with the median of follow up time 18 months after resection.

Immunohistochemistry

The determination of IDH1 and MGMT status by immunohistochemistry was carried out at Dr. Hasan Sadikin Hospital, Bandung (n = 42); Dharmais National Cancer Hospital, Jakarta (n = 32); Siloam Hospital, Lippo Village, Karawaci (n = 54); and Dr. Kariadi Hospital, Semarang (n = 42).

Formalin-fixed paraffin embedded tumor specimens were analyzed by IHC using 4 µm sections. Antigen was retrieved in 10 mM citrate buffer (pH 6.0) at 95°C to 122°C for 15 minutes. Slides (sections) were deparaffinized by xylene changes. Endogenous peroxidase activity was blocked with 0.3% H₂O₂ in methanol for 20–30 min. Slides were incubated at 4°C overnight with a mouse antibody against human MGMT (Santacruz, Biotechnology, California, USA) used at final dilution of 1:250 or anti-human IDH1 R132H mutant specific AB (GTX57185, Genetex, California, USA) used at 1:200 dilution. Diaminobenzidine was used to catch the signal followed by a nuclear stain (hematoxylin: blue).

Assessment of MGMT expression in tumor sections was performed by two independent pathologists who were blinded to methylation pattern and other parameters. Staining for MGMT protein was considered positive when uniform MGMT staining was displayed in the nuclei of cells. Staining that was restricted to the cytoplasm and granular nuclear reactivity was considered negative. IDH1 mutant staining was considered positive when uniform IDH1 staining was displayed in the cytoplasmic of cells.

DNA extraction

Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) and fresh tissue specimens for retrospective samples at Dr. Sardjito Hospital, Yogyakarta (n = 157). For FFPE tissue specimens, following deparaffinization of unstained tissue sections, DNA was isolated using the QIAamp DNA FFPE Tissue Kit (QIAGEN, Cat. #56404, Hilden, Germany) according to the manufacturer’s instructions. DNA from fresh glioma tissue was extracted using the Quick DNA FFPE MiniPrep Kit (Zymo Research, USA). The NanoVue Plus spectrophotometer (GE Healthcare Life Sciences, Pittsburgh, PA, USA) was then used to assess the quantity of recovered DNA.

PCR amplification and sequencing analysis

Polymerase chain reaction (PCR) was performed to amplify the codons R132 and R172 of the exon 4 of the IDH1 and IDH2 genes, respectively. The IDH1 forward (5’-ACC AAA TGG CAC CAT ACG A-3’) and reverse (5’-GCA AAA TCA CAT TAT TGC CAA C-3’) primers generated a 130 base pair (bp) PCR product while the IDH2 forward (5’-GCT GCA GTG GGA CCA CTA TT-3’) and reverse (5’-TGT GGC CTT GTA CTG CAG AG-3’) primers generated a 293 bp PCR product.

PCR reactions were set at a total volume of 25 µL containing 2 µL of genomic DNA, 3.45 µL of Taq DNA Polymerase (Invitrogen, Thermo Fisher Scientific, Cat. #10342020, Waltham, MA, USA), 0.2 µL of dNTP (Thermo Scientific, Thermo Fisher Scientific, Cat. #R0191, Waltham, MA, USA), and 1 µL of each primer. The PCR was performed using Veriti Thermal Cycler (Applied Biosystem, Thermo Fisher Scientific, Cat. #4375786, Waltham, MA, USA) under the following conditions: initial denaturation at 95oC for 2 minutes followed by 40 cycles of denaturation at 95oC for 30 seconds, annealing at 53oC (IDH1) or 56oC (IDH2) for 30 seconds, and extension at 72oC for 2.5 minutes. The amplified products were then visualized using 2% agarose gel electrophoresis to confirm the presence of a single band of the predicted size. After purification with MinElute PCR Purification Kit (QIAGEN, Cat. #28004, Hilden, Germany), sequencing of the products in both sense and antisense directions was performed using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystem, Thermo Fisher Scientific, Cat. #4337455, Waltham, MA, USA). Each sample was categorically defined as positive or negative for IDH1/2 gene mutation based on the sequencing results.⁵

Methylation-specific qRT-PCR

Bisulfite conversions of genomic DNA to convert unmethylated cytosine to uracil were performed using the EZ DNA Methylation-Gold Kit (Zymo Research Cat o. D5005 Lot No. ZRC 200814). Up to 2,000 ng of DNA was treated to obtain adequate converted DNA for MGMT promoter methylation status analysis using a quantitative real-time PCR method as described elsewhere.⁵

Statistics

The patients were followed up to determine the Overall survival (OS) from the date of the diagnosis. Different tests for homogeneity of proportions including Chi square and Kaplan Meier analysis to evaluate survival outcome probabilities were used to determine significance of the distribution patterns with respect to different clinical parameters. Statistical analysis was performed by using Graphpad Prism v8.0. Statistical significance was set at the level of p < 0.05.

We enrolled 327 patients diagnosed as WHO criteria of astrocytic gliomas; 53 specimens were diagnosed as grade II, 29 as grade III, and 245 as grade IV (glioblastoma). At 36 months follow-up, 82.46% of subjects with WHO grade II and 72.24% of subjects with WHO grade III survived compared to subjects with 29%.23 WHO grade IV. The overall survival rate in WHO grade II, grade III vs. grade IV, had a significant difference in HR 2.41 [0.87–6.65] and HR 5.34 [2.61–10.91] (p < 0.0001) (Fig. 1). We made a similar comparison based on the KPS score. Subjects with a KPS score > 70 had a higher survival rate than those with a KPS score ≤ 70 (Median survival rate 35 months vs. 16 months, HR 1.64 [1.08–2.50]; p = 0.0208) (Fig. 2). Patient characteristics are summarized in Table 1.

Table 1

Patient Characteristics (N = 327)
Characteristics	IDH1 Wildtype	IDH1 Mutant	p-Value
Age	44.48 ± 16.77	42.33 ± 12.45	0.0354
Gender			0.0982
Male	113	74
Female	97	43
KPS score	57.66 ± 17.75	63.84 ± 21.53	0.0223
WHO Grade			< 0.0001
II	0	53
III	0	29
IV	210	35
MGMT Status			< 0.0001
Methylated	73	86
Unmethylated	137	31

A total of 327 patients were included in the study, 117 with IDH1 Mut and 210 with IDH1 WT. At 36 months follow-up, 63.87% of subjects with IDH1 Mut survived compared to 30.44% in subjects with IDH1 WT (HR 2.13 [1.51–3.00]; p < 0.0004) (Fig. 3); 80.33% of subjects with IDH1 Mut MGMT methylated, 68.02% of subjects with IDH1 WT MGMT methylated, 32.92% of subjects with IDH1 Mut MGMT unmethylated; survived compared to in subjects with 21.35% IDH1 WT MGMT unmethylated, the overall survival rate had a significant difference (p < 0.0001) (Fig. 4). The overall survival rate in IDH1 Mut MGMT methylated vs. IDH1 Mut MGMT unmethylated had a significant difference (HR 14.20 [5.82–34.64]; p < 0.0001) and IDH1 WT MGMT methylated vs. IDH1 WT MGMT unmethylated also had a significant difference (HR 2.55 [1.72–3.78]; p = 0.0003) (Fig. 5A, B).

This is the first multicenter study ever conducted in Indonesia; IDH1 and MGMT status were examined in 327 specimens that diagnosed with WHO-based diagnosis for glioma tumors. A total of 117 of the 327 samples analyzed turned out to have heterozygous mutations in the 132 IDH1 codon that specifically changed from arginine to histidine; Omer et al., showed a variation in the percentage of mutant IDH1 R132H for gliomas from several countries in Asia ¹¹ Dwianingsih et al.,¹² in 2017, showed that IDH1 mutations are highly identified in Indonesian glioma patients, as high as 74% (37/50), and significantly correlated with grading.^12,13 Study results suggest that most adult gliomas in Indonesia are wildtype, encouraging demand for adjuvant therapy facilities.

Cytosolic IDH1 mutation on the diffuse astrocytic tumor was one of the main biomarkers for the diagnosis and prognosis of glioma.^14–17 In this study, an immunochemistry test used anti-IDH1R132H staining on post-operative or biopsy paraffin blocks. Mutation of IDH1 on codon 132 was identified in 50 out of 126 samples (39.7%).¹⁰ Several studies observed the catalysis of minor substitution of amino acids R132S, R132C, E132G, and R132L in patients with positive IDH1-R132H staining. Similar phenomena were observed in patients with WHO grade II, III, and WHO grade IV (glioblastoma).¹⁸

Regarding overall survival, with a total of 36 months follow-up in our study, 63.87% of subjects with IDH1 mutant survived compared to 30.44% in subjects with IDH1 wild type. An observational study conducted by Tabei et al., in 2020 with a total of 174 patients with a newly diagnosed glioma showed a median OS after first progression at 13.5 and 10.5 months, respectively, for mutant IDH1 and wildtype IDH1.¹⁹ The evidence of better OS for IDH1 mutant patients is also supported by a meta-analysis of 55 observational studies conducted by Cheng in 2013.²⁰

Age

Molinaro et al., in 2019 found that patients diagnosed with diffuse astrocytic glioma at a relatively young age are most likely IDH-mutant astrocytoma. On the other hand, individuals diagnosed at an older age are most likely to have an IDH-wild type astrocytoma. As previously mentioned, the IDH-mutant has better overall survival.²¹ Therefore, we might have a rough idea about the type and patient prognostic by knowing the age at diagnosis. Our study also found a younger population within the IDH1 mutant cohort than in the IDH1 wildtype cohort (42.33 ± 12.45 vs. 44.48 ± 16.77, respectively). Other studies also revealed that IDH1 mutant was found in younger patients with significant differences to those with IDH1 wild type.

WHO Grade

WHO classification of adult diffuse gliomas has been modified several times.^1,2 The evidence has suggested that IDH1 WT is associated with TERT promoter mutation, EGFR amplification, a gain of chromosome 7, and chromosome 10 deletion, which belongs to the hallmarks of glioblastoma.^2,21 The clinical behavior and genetic profile of IDH1 WT lead to a consensus for grouping all IDH1 WT as glioblastoma (WHO Grade IV) for easing the clinical trial and encouraging more aggressive treatment for this group of patients.^2,21

Karnofsky Performance Scale (KPS)

KPS was a widely used performance assessment of cancer patients. A low KPS score is a predictor of survival.²² Our findings support its use in long-term prognosis (p = 0.0208). At the time of surgery, most patients had a KPS score greater than 70, while a small group with a KPS score lower than 70 had a much worse survival rate. IDH1 wild type exhibited a lower KPS than IDH1 mutant patients.²³ From the author's perspective, only a few studies compared KPS to determine patient prognostic in either IDH mutant or wild type. However, Mandel et al., showed that low KPS was found more frequently in the IDH-1 wild type than in the IDH1 mutant.⁴ On the other hand, a retrospective study conducted by Zheng et al., showed that the mean length of overall survival was greater in patients with higher KPS scores rather than in patients with lower KPS scores.²⁴

MGMT Status

Temozolomide is known to disrupt DNA replication in tumors by alkylating the guanine. The enzyme O-6-methylguanine-DNA methyltransferase (MGMT) removes alkyl groups from guanine at the O6 site, counteracting TMZ. Methylation of the MGMT increasing TMZ effectiveness.^25,26 This disparity in the biological importance of MGMT promoter methylation is most likely due to the varied distribution of IDH mutations among these tumors rather than the grade of malignancy itself.²³ In terms of overall survival, with a total of 36 months follow-up in our study, 80.33% of subjects with IDH1 Mut MGMT methylated, 68.02% of subjects with IDH1 WT MGMT methylated, 32.92% of subjects with IDH1 Mut MGMT unmethylated; survived compared to in subjects with 21.35% IDH1 WT MGMT unmethylated.

Other biomarkers

Molecular diagnostics can produce patient-specific medicines that target distinct oncogenic pathways, whereas histopathological analysis can provide a generic classification of glioma grade.²⁷ Chromosome 7 amplification (associated with chromosome 10 deletion) and EGFR amplification were found in 100 percent and 97 percent of classic glioblastoma cases, respectively.²⁸ There were also NF1-containing localized hemizygous deletions at 17q11.2 in most mesenchymal cases and elevated expression of genes linked to necrosis and inflammation.²⁹ There have also been other biomarkers that have emerged. Periostin and PDL-1 are of particular interest.

Periostin is a matricellular fascilin-like protein first identified as a periodontal ligament component.²⁷ Despite the early identification that the periostin gene is one of the most elevated genes in GBM compared to the normal brain, more is needed to know about periostin's prognostic or functional importance in human gliomas. Its expressions were examined by quantitative real-time PCR and immunohistochemistry.³⁰ Faried et al., conducted a meta-analysis that showed that high periostin expression might help predict the overall survival of the patients.³¹ These findings confirm periostin's possible role in glioma malignancy; however, the methods by which periostin contributes to glioma malignancy need to be investigated further.

Programmed Death Ligand-1 (PDL-1) is a protein encoded in the CD274 gene.³² The expression of PDL-1 can be detected by immunohistochemistry. A study by July et al., stated that high expression of PDL-1 is associated with shorter survival in gliomas.³⁴ Both anaplastic astrocytoma and GBM groups showed better survival when PD-L1 expression was negative (estimated survival was 27 months within the range 17.9–36.1 months and 12 months within the range 9.3–14.7, respectively) when compared to PD-L1 positive group (estimate survival was 17 and 4.5 months, respectively).³³ L-type amino acid transporter-1 (LAT-1) is a recently expressed biomarker to predict prognosis in gliomas.³⁴ Study conducted by Faried et al., showed that high expression of LAT-1 is associated with poor survival in glioma patients; hence, it can increase proliferation in malignant glial cells and contribute to further activation of PDL-1, which further increases the proliferation of glioma.³⁵

Study limitation

This study has several intrinsic limitations. Firstly, this is due to its retrospective character, the possibility for inherent bias, as well as the small size of the cohort, given the unusual nature of the researched entity. Although various risk variables for the development of diffuse astrocytic gliomas, such as age, gender, KPS, WHO grading, and molecular analysis, were considered.

Immunohistochemical staining of the IDH1-R132H mutant was able to differentiate the survival rate between the IDH1 mutant and IDH1 wildtype groups. Hence, this examination could be used as an alternative to the targeted sequencing of IDH1.

GBM

Glioblastoma

IDH1

Isocitrate Dehydrogenase-1

R132H

A substitution Mutations at position 132, changing from arginine to histidine

MGMT

The enzyme O-6-methylguanine-DNA methyltransferase

WHO

World Health Organization

KPS

Karnofsky Performance Score

Hazard Ratio

EGFR

Epidermal Growth Factor Receptor

NF1

Neurofibromin 1

PDL-1

Programmed Death Ligand-1

LAT-1

L-Type Amino Acid Transporter 1

PCR

Poly Chain Reaction

Conflict of Interest

All authors declares that there is no potential conflict of interest relevant to this article.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Authors’ contributions

Author contributions to the study and the manuscript preparation. Conception and design

All; Methodology Faried A, Hermanto Y, Halim D; Formal Analysis Faried A, Hermanto Y, Halim D; Writing - Original Draft Faried A, Hermanto Y; Writing - Review and Editing All; Supervision All. Funding Acquisition, Faried A. All authors had full access to the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgement

Faried A. supported by the Grants-in-Aid from Universitas Padjadjaran, Bandung, with No. 2203/UN6.3.1/PT.00/2022 for Academic Leadership Grant.

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No competing interests reported.

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The Overall Survival Rate Prognosis in Diffuse Astrocytic Patients Based on Isocitrate Dehydrogenase-1 Mutation Status (IDH1 R132H): An Indonesian Multicenter Study

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Abstract

Figures

Introduction

Methods

Subjects

Immunohistochemistry

DNA extraction

PCR amplification and sequencing analysis

Methylation-specific qRT-PCR

Statistics

Results

Discussion

Age

WHO Grade

Karnofsky Performance Scale (KPS)

MGMT Status

Other biomarkers

Study limitation

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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