Nationwide Genomic Data Analysis of Central Nervous System Tumors in Japan based on C-CAT Database

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In Japan, three tissue-based CGPTs, FoundationOne® CDx, GenMineTOP, and NCC OncoGuide™, are reimbursed under public health insurance. However, their comparative performance in central nervous system (CNS) tumors remains unclear. Methods We conducted a nationwide, retrospective analysis using data from the Center for Cancer Genomics and Advanced Therapeutics database. A total of 1,151 patients with CNS tumors who underwent CGPT between August 2023 and April 2025 were included. Patient characteristics, genetic mutations, tumor mutation burden, and numbers of drug and clinical trial suggestions were compared across the three CGPTs. Results FoundationOne® CDx detected significantly more mutations and copy number alterations than GenMineTOP and NCC OncoGuide. It also proposed more off-label drugs and domestic clinical trials. Conversely, GenMineTOP demonstrated the highest detection rate of gene fusions (9.6%), including KIAA1549-BRAF, FGFR3-TACC3, and EGFR-SEPT14, and PTPRZ1-MET. Furthermore, GenMineTOP identified germline mutations in 4.6% of patients, commonly involving TP53, BRCA2, and MSH6. Conclusion FoundationOne® CDx exhibits greater number of mutations, copy number alterations, and generating therapeutic suggestions, while GenMineTOP excels in identifying fusion genes and germline variants. These findings underscore that each CGPT possesses distinct analytical strengths, and the choice of platform may influence the genomic landscape and therapeutic opportunities identified in CNS tumor patients. Comprehensive genomic profiling test Foundation One GenMineTOP NCC OncoGuide Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 INTRODUCTION Advancements in molecular genetics of tumorigenesis have underscored the growing significance of molecular classification in cancer diagnosis, treatment selection, and prognostic assessment. Comprehensive genomic profiling test (CGPT), utilizing next-generation sequencing (NGS), enables the analysis of numerous cancer-related genes within a tumor to identify mutations, fusions, copy number variations, and other genomic abnormalities. This approach aims to detect a broad spectrum of genomic changes that may drive tumor development, thereby leading the implementation of personalized therapeutic strategies [ 1 ]. In Japan, three CGPTs for tissue specimen are currently covered under the public health insurance system: the FoundationOne® CDx Cancer Genome Profile (FoundationOne CDx) and the OncoGuide™ NCC Oncopanel System (NCC OncoGuide) available from 2019, and the GenMineTOP Cancer Genome Profiling System (GenMineTOP) available from 2023. According to the clinical practice guidance for NGS in cancer diagnosis and treatment, edition 2.1 [ 2 ], CGPT is indicated for patients with solid tumors for which there is no standard treatment or those with solid tumors in whom locally advanced disease or metastasis is seen and who have completed standard treatment (including patients expected to complete the treatment), those who are judged by the attending physician to have a strong likelihood of being suitable for chemotherapy after the test according to the chemotherapy guidelines of the relevant academic society, based on factors such as their general condition and organ function. However, there are no established instruction which CGPT to select, therefore, the choice of CGPT is left to the discretion of the physician. When patients underwent CGPT, their anonymized clinical and genomic data are collected and centralized at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT). This datacenter promotes broad utilization of its aggregated data by hospitals, academic institutions, and industry partners [ 3 ]. While the utility of CGPT in detecting somatic and germline mutations in diffuse gliomas has been previously reported [ 4 ], no studies to date have specifically compared the differences in results among the CGPTs in patients with central nervous system (CNS) tumors. This study utilized the C-CAT database to examine and compare patient characteristics, genetic mutation profiles, and the corresponding therapeutic recommendations and clinical trials among the three CGPTs available for CNS tumor patients since 2023. PATIENTS AND METHODS Data collection This study was a nationwide retrospective analysis of patients with CNS tumors in Japan. Genomic and clinical information registered in the C-CAT database between August 2023, when GenMineTOP began its service under insurance coverage, and April 2025 were included. Collected data included patient age, sex, pathological diagnosis, type of genomic panel used, genetic alterations, suggested Pharmaceuticals and Medical Devices Agency (PMDA) and the U.S. Food and Drug Administration (FDA) off-label drugs, proposed domestic clinical trials, and tumor mutation burden (TMB; Mutations/Megabase, Muts/Mb). The pathological diagnoses were obtained directly from the C-CAT database and were not centrally reviewed. Therefore, some diagnoses may not fully reflect the latest WHO classification criteria. For the genetic alterations, only those with evidence level F, defined as “known to be involved in oncogenesis”, on the C-CAT report were analyzed to minimize the discrepancies for genetic alterations subject to reporting among CGPTs. Mutation data were obtained from the “small scale variants” category of the C-CAT database. Comprehensive genomic profiling tests Main characteristics of three CGPTs are summarized in Supplementary Table 1. Briefly, FoundationOne CDx was developed by Foundation Medicine (Roche) and approved in Japan in June 2019. It targets 324 DNA alterations in cancer-related genes using NGS. The NCC OncoGuide analyzes 124 DNA alterations using NGS with tumor–normal paired analysis and is applicable to small samples, including biopsy specimens. Lastly, GenMineTOP, developed and provided by the University of Tokyo and Konica Minolta REALM, Inc., analyzes 737 DNA alterations and 455 RNA alterations via NGS. Unlike FoundationOne CDx, which analyzes tumor tissue only, GenMineTOP performs tumor-normal paired analysis, simultaneously sequencing both tumor tissue and the patient’s normal blood sample, allowing for high-confidence distinction between somatic and germline mutations. Additionally, GenMineTOP reports only focal gene amplifications as copy number alterations (CNAs) and does not provide information on gene losses, although the result of focal CNAs are available as graphical supplementary data. Statistical analysis Comparison of age, the number of genetic alterations detected, the number of drug and clinical trials recommended, and TMB between three groups was evaluated using the Kruskal-Wallis test. The association of the number of somatic mutations and TMB was investigated by simple linear regression model. Statistical analyses were performed using GraphPad Prism 10 (GraphPad Software, Inc., La Jolla, California, USA). Statistical significance was defined as a P-value of <.05. Ethics approval All CGPTs were conducted under the national health insurance system. This retrospective study analyzed data originally obtained for clinical purposes. Written informed consent for the use of genomic and clinical information in research was obtained from all participants. The study received approval from the internal review board of the National Cancer Center (approval number: 2020-067) and authorized by the Information Utilization Review Board of C-CAT for secondary data use. RESULTS Patient demographics A total of 1,151 CGPTs were performed during the study period. Among them, 563 cases were tested with FoundationOne CDx, 542 with GenMineTOP, and 46 with NCC OncoGuide (Fig 1a). In terms of test distribution, FoundationOne CDx accounted for 77.7% of tests in 2023, while GenMineTOP accounted for 17.5%. However, by 2025, GenMineTOP had increased to 69.3%, while FoundationOne CDx declined to 27.4%, suggesting that GenMineTOP has gained an increasing share of CGPT utilization in Japan over these two years (Fig 1b). The median ages of patients undergoing FoundationOne CDx, GenMineTOP, and NCC OncoGuide testing were 49.0, 49.0, and 44.5 years, respectively, with no significant differences among the groups (Fig 2a). The proportions of male patients were 52.0%, 54.6%, and 47.8% in the FoundationOne CDx, GenMineTOP, and NCC OncoGuide groups, respectively, with no significant difference in sex distribution (p = 0.531; Fig 2b). Across the entire cohort, glioblastoma (GBM) represented the most frequent pathological diagnosis, comprising 39.44% of cases, followed by astrocytoma (9.64%), diffuse gliomas (8.17%), pilocytic astrocytoma (4.87%), gliomas, glioneuronal and neuronal tumours (4.78%), meningioma (4.78%), adult-type gliomas (2.69%), diffuse midline glioma, H3K27-altered (2.61%), and others (23.02%) (Fig 3). The three predominant diagnoses, GBM, astrocytoma, and diffuse gliomas, were observed at comparable frequencies across all CGPT groups. Number of mutations The median number of mutations with evidence level F detected per patient was 2 with FoundationOne CDx and GenMineTOP, and 1 with NCC OncoGuide, respectively. FoundationOne CDx identified a significantly higher number of mutations compared to the other two CGPTs (p < 0.0001 and p < 0.0001; Fig 4a), and GenMineTOP detected significantly greater number of mutations compared to NCC OncoGuide (p = 0.0003). The most frequently detected mutations in both FoundationOne CDx and GenMineTOP were TP53 , TERT promoter, NF1, PTEN, EGFR, and IDH1 mutations (Fig 4b). Subanalysis targeting adult GBM (21 years old or older) patients revealed the median number of mutations with the evidence level F detected by Foundation One CDx, GenMineTOP, and NCC OncoGuide per patient was 3, 2, and 1, respectively. There was no significant difference between FoundationOne CDx and GenMineTOP (p = 0.29; Supp Fig 1a), but NCC OncoGuide detected significantly smaller number of mutations compared to Foundation One (p = 0.0041), and GenMineTOP (p = 0.0028). The most frequently detected mutations were TERT , TP53, PTEN, EGFR, and NF1, which were commonly identified by both FoundationOne and GenMineTOP (Supp Fig 1b). The median number of detected focal CNAs per patient was 2 for FoundationOne CDx, and 0 for GenMineTOP and NCC OncoGuide. FoundationOne CDx again detected a significantly higher number of focal CNAs compared to the other two tests (p < 0.0001 for both comparisons; Fig 5a). While the most frequently detected CNAs in FoundationOne CDx were CDKN2A loss and CDKN2B loss, these deletions were not reported in GenMineTOP (Fig 5b). As previously noted, GenMineTOP does not report gene deletions such as CDKN2A/B loss or PTEN loss. However, in one case from our institution involving a 46-year-old female patient with astrocytoma, IDH-mutant, CNS WHO grade 4, the supplementary information in the GenMineTOP report did indicate a CDKN2A/B homozygous deletion, even though it was not explicitly stated in the supplementary report. This deletion was further confirmed by our in-house targeted sequencing. Additionally, broad CNAs such as chromosome 10 loss in a 51-year-old male patient with molecular GBM, and 1p/19q codeletion in a 28-year-old male patient with oligodendroglioma, CNS WHO grade 3, were indicated in the supplementary information in the GenMineTOP report (Fig 6). Regarding gene fusions, the detection frequencies were 7.5% for FoundationOne CDx, 9.6% for GenMineTOP, and 8.7% for NCC OncoGuide (Fig 7a). The most commonly identified fusions across the three CGPTs were KIAA1549–BRAF and FGFR3–TACC3 . In addition to these, GenMineTOP detected glioma related gene fusions such as EGFR–SEPT14 and PTPRZ1–MET compared with FoundationOne CDx (Fig 7b). It is important to note that FoundationOne CDx, which reports gene fusions based solely on DNA sequencing without considering the direction of transcription, has frequently reported bidirectional configurations such as KIAA1549–BRAF and BRAF–KIAA1549 in the same case, likely leading to the inadvertent inclusion of non-oncogenic configurations like BRAF–KIAA1549 . In contrast, GenMineTOP consistently reported a single, correctly oriented fusion configuration, directly validated by RNA sequencing, which enables the accurate determination of the transcription direction. Germline mutations Among the 542 GenMineTOP cases, 27 germline mutations were identified in 25 patients (4.6%). The most frequently detected germline mutation was TP53 (n = 9, 1.66%), followed by BRCA2 (n = 3, 0.55%), and MSH6 (n = 3, 0.55%, Fig 8). Proposed drugs and clinical trials The median number of proposed drugs and clinical trials per patient varied across the three CGPT platforms. For PMDA off-label drugs, the medians were 2 for FoundationOne CDx, 1 for GenMineTOP and NCC OncoGuide (Fig 9a). For FDA off-label drugs, the medians were 3, 2, and 2, respectively (Fig 9b). Patients in the FoundationOne CDx group received significantly more proposals for PMDA and FDA off-label drugs compared to those in the GenMineTOP group (p = 0.0006, p = 0.0002). The median number of proposed domestic clinical trials was 2 for FoundationOne CDx, 1 for GenMineTOP and NCC OncoGuide. Patients in the FoundationOne CDx group received significantly more domestic clinical trial suggestions than those in the GenMineTOP group (p < 0.0001) and NCC OncoGuide (p = 0.04, Fig 9c). The proposed drugs were further evaluated. The frequently proposed drugs were everolimus (24.3%), temsirolimus (20.8%), pazopanib hydrochloride (19.5%), lenvatinib (14.6%), cabozantinib (14.0%), capivasertib and fulvestrant (13.3%), sorafenib (12.3%), doxorubicin hydrochloride (11.6%), imatinib mesylate (10.8%), and panitumumab (9.6%) in FoundationOne CDx and capivasertib and fulvestrant (14.2%), Lenvatinib (14.0%), sorafenib (13.8%), everolimus (13.7%), temsirolimus (13.3%), pazopanib hydrochloride (13.1%), selumetinib (12.5%), panitumumab (11.8%), cabozantinib (10.3%), temozolomide + vandetanib (9.2%) in GenMineTOP (Fig 9d and supplementary table 2). When we examined the representative drugs proposed and the gene alterations on which their recommendations were based, a considerable number of cases showed PTEN loss. As mentioned above, this alteration was identified only by FoundationOne, which likely explains the significantly higher number of drug recommendations generated by FoundationOne compared to GenMineTOP (Supplementary table 3). Tumor mutation burden The median values of TMB were 2.0, 2.1, and 2.3 Muts/Mb for FoundationOne CDx, GenMineTOP, and NCC OncoGuide, respectively (Fig 10a), with no statistically significant differences among the three panels. Plotting TMB against the number of mutations for each case yielded slopes of 1.21, 0.51, and 2.54, with corresponding coefficients of determination (R²) of 0.928, 0.998, and 0.881, respectively (Fig 10b). DISCUSSION Analysis of C-CAT data revealed a growing number of GenMineTOP cases for CNS tumors following its inclusion in public health insurance coverage in 2023. Two primary factors may account for the expanding market share of GenMineTOP within Japan’s CGP landscape. First, as a domestically developed CGPT, GenMineTOP enables genomic and clinical data to be analyzed and managed entirely in the home country, thereby minimizing the risk of data being transferred overseas. Second, GenMineTOP was designed to detect a wider range of genetic alterations in both DNA and RNA compared to the other two CGPTs, with the expectation of yielding more comprehensive and clinically actionable information. While the first rationale appears valid, the second was unfortunately not supported by the findings of this study. Despite initial expectations, our results did not demonstrate a significant advantage for GenMineTOP in terms of either the number or clinical relevance of the detected alterations. Our results showed that FoundationOne CDx detected significantly more CNA compared to GenMineTOP and NCC OncoGuide. A notable limitation of GenMineTOP is that it reports only gene amplifications and therefore does not capture gene loss events. This difference may have contributed to the result that FoundationOne CDx could proposed a significantly greater number of PMDA off-label drugs and domestic clinical trials. Furthermore, given that such deletions, particularly CDKN2A/B homozygous deletions, are critical for the molecular diagnosis of CNS tumors, the absence of this information in the GenMineTOP report, despite being available in supplementary information, represents a significant shortcoming that requires prompt rectification. In addition to CNAs, FoundationOne CDx also detected significantly more mutations compared to the other two CGPT. The reasons underlying the discrepancies in detection rates among the three CGPT remain unclear. Since, as of July 2023, reimbursement for CGPT is limited to one test per patient over their lifetime, patients are unable to undergo both FoundationOne CDx and GenMineTOP. Therefore, further academic investigation is urgently needed to clarify the differences in detection capabilities among CGPTs and to guide optimal test selection. In contrast, GenMineTOP is capable of detecting gene fusions with proper orientation, including KIAA1549-BRAF , FGFR3-TACC3 , EGFR-SEPT14 , and PTPRZ1-MET . KIAA1549-BRAF fusion is found in 77.3–78.7% of pilocytic astrocytoma [ 5 , 6 ] and known as a molecular profile characteristically altered [ 7 , 8 ]. Only the KIAA1549-BRAF fusion is oncogenic, and therefore its configuration is critically important. In this regard, GenMineTOP, which determines the precise configuration of gene fusions through RNA sequencing, is considered superior to FoundationOne CDx. FGFR3-TACC3 and EGFR-SEPT14 , are gene fusions commonly found in GBM with frequencies of 4.1% [ 9 ] and 4% [ 10 ]. Furthermore, although not explicitly stated in the report, the supplementary data of GenMineTOP demonstrate key chromosomal alterations, including 1p/19q codeletion characteristic of oligodendroglioma and whole chromosome 7 gain with chromosome 10 loss, which define molecular GBM. These alterations are essential for accurate tumor classification, and omission of such information may lead to under-diagnosis. In this study, the frequency of germline mutations with evidence level F among patients with CNS tumors was found to be 4.6%, which is lower than the previously reported frequencies of 7.7% in patients with diffuse gliomas [ 4 ], and 6.2% in patients with malignant solid tumors in Japan [ 11 ]. This lower frequency is likely because C-CAT designates evidence F only to germline mutations listed in the American College of Medical Genetics and Genomics (ACMG) statement [ 12 ], thereby excluding germline mutations not included on the ACMG statements, such as NF1 and POLE . The observed difference in the slope of the plotted relationship between TMB and somatic mutations in FoundationOne CDx and GenMineTOP can be attributed to differences in the definition of TMB between the two CGP platforms. According to the official documentation of FoundationOne CDx, TMB is defined as “the number of synonymous and nonsynonymous mutations with an allele frequency of 5% or higher.” In contrast, GenMineTOP defines TMB as “the number of nonsynonymous mutations with an allele frequency of 5% or higher and a read depth of at least 100.” Synonymous mutations are nucleotide substitutions that do not alter the resulting amino acid sequence, whereas nonsynonymous mutations lead to an amino acid change. The inclusion of synonymous mutations in FoundationOne CDx, but not in GenMineTOP, likely accounts for the discrepancy in TMB values and their relationship with the number of detected somatic mutations. One limitation of this study was that this study did not involve direct matched case comparisons among the three CGPTs. As such, differences in the detection of genetic alterations or therapeutic suggestions may be influenced by variations in patient backgrounds or tumor characteristics, rather than intrinsic differences in assay performance. Also, the retrospective nature of the study, relying on real-world registry data, may introduce selection bias or inconsistencies in data quality. Furthermore, differences in clinical practice patterns among institutions could have influenced CGPT selection and reporting. Lastly, the analysis was based on the C-CAT database summary reports, without access to raw sequencing data. Therefore, it was not possible to verify or reanalyze variant calls, especially in borderline or discordant cases. CONCLUSION FoundationOne exhibits greater number of mutations, CNAs, and generating therapeutic suggestions, while GenMineTOP excels in identifying fusion genes and germline variants. These findings underscore that each CGPT possesses distinct analytical strengths, and the choice of platform may influence the genomic landscape and therapeutic opportunities identified in CNS tumor patients. Declarations ACKNOWLEDGMENTS None. CONFLICT OF INTEREST The authors have no conflict of interest. DATA AVAILABILITY STATEMENT The data sets used and/or analyzed during this study are available from the corresponding author on reasonable request. FUNDING INFORMATION This study did not receive any specific grants or financial support from funding agencies in the public, commercial, or not-for-profit sectors. ETHICS STATEMENT The study received approval from the internal review board of the National Cancer Center (approval number: 2020-067) and authorized by the Information Utilization Review Board of C-CAT for secondary data use. Informed Consent: Written informed consent for the use of genomic and clinical data for research purposes. The tests were performed under regular medical insurance. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. References Pankiw M, Brezden-Masley C, Charames GS (2023) Comprehensive genomic profiling for oncological advancements by precision medicine. 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Genet Med 27 (8):101454. doi:10.1016/j.gim.2025.101454 Supplementary Files SupplementaryFigure1251203.docx SupplementaryTable1251022.docx SupplementaryTable2251107.docx SupplementaryTable3251203.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revisions 20 Feb, 2026 Reviewers agreed at journal 06 Jan, 2026 Reviewers invited by journal 06 Jan, 2026 Editor assigned by journal 04 Jan, 2026 First submitted to journal 30 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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group.\u003c/p\u003e","description":"","filename":"Figure2251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/e8473ea25a7f5c550708e822.png"},{"id":100365374,"identity":"fc55e2e4-fe6e-4ec6-a4ba-100d655f3ce7","added_by":"auto","created_at":"2026-01-16 07:55:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5817327,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of pathological diagnoses across CGPT groups. \u003c/strong\u003eGlioblastoma is the most common diagnosis, accounting for 39.44% of all cases, followed by astrocytoma (9.64%) and diffuse gliomas (8.17%).\u003c/p\u003e","description":"","filename":"Figure3251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/4124705c7520a4fe2e7ca6e3.png"},{"id":100364547,"identity":"6ca05109-3b75-40eb-bbe5-b7c4461f0058","added_by":"auto","created_at":"2026-01-16 07:53:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4167808,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of \u003c/strong\u003emutations\u003cstrong\u003e across the three CGPTs. \u003c/strong\u003e(A) The number of mutations per patient detected by FoundationOne CDx, GenMineTOP, and NCC OncoGuide.\u003cstrong\u003e \u003c/strong\u003e(B) Representative somatic and germline mutations identified by each CGPT are listed for comparison.\u003c/p\u003e","description":"","filename":"Figure4251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/482ea16ba68c726d692bd460.png"},{"id":100365501,"identity":"b713702a-d3e2-46ba-a208-e8a687996de6","added_by":"auto","created_at":"2026-01-16 07:55:16","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":4458645,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of copy number alterations (CNAs) across the three CGPTs. \u003c/strong\u003e(A) The number of CNAs per patient detected by FoundationOne CDx, GenMineTOP, and NCC OncoGuide.\u003cstrong\u003e \u003c/strong\u003e(B) Representative CNAs identified by each CGPT are listed for comparison.\u003c/p\u003e","description":"","filename":"Figure5251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/effc535fd4047bfd63d09971.png"},{"id":100093989,"identity":"592ca604-3b1a-4993-a5bb-5f2cb270a259","added_by":"auto","created_at":"2026-01-13 01:28:00","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":16507044,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative cases with gene deletions not reported in GenMineTOP. \u003c/strong\u003eThree representative cases are shown in which clinically significant gene deletions are not reported in the main GenMineTOP results but are indicated in the supplementary report.\u003c/p\u003e","description":"","filename":"Figure6251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/3fc170287579c0035197bc10.png"},{"id":100364908,"identity":"629b3be5-99ea-4016-9e4f-7161515e07dc","added_by":"auto","created_at":"2026-01-16 07:54:28","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1209703,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of gene fusions across the three CGPTs. \u003c/strong\u003e(A) The frequency of gene fusions detected by FoundationOne CDx, GenMineTOP, and NCC OncoGuide.\u003cstrong\u003e \u003c/strong\u003e(B) Representative gene rearrangements identified by each CGPT are listed for comparison.\u003c/p\u003e","description":"","filename":"Figure7251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/db1e00df28b63e2531229f94.png"},{"id":100364514,"identity":"c3c2eba8-c76a-46af-b6bd-2a1ce51ff944","added_by":"auto","created_at":"2026-01-16 07:53:49","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":60954,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGermline mutations detected in GenMineTOP. \u003c/strong\u003eThe frequency of germline mutations with evidence level F detected in GenMineTOP.\u003c/p\u003e","description":"","filename":"Figure8251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/3d3a6cc548298ac3ca1cead0.png"},{"id":100365025,"identity":"a2c0f9a0-0dec-42e2-9c0f-0815c1f159a7","added_by":"auto","created_at":"2026-01-16 07:54:36","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":4051688,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of drugs and clinical trials recommended by each CGPT. \u003c/strong\u003e(A) The number of PMDA off-label drugs per patient proposed by FoundationOne CDx, GenMineTOP, and NCC OncoGuide.\u003cstrong\u003e \u003c/strong\u003e(B) The number of FDA off-label drugs per patient proposed by FoundationOne CDx, GenMineTOP, and NCC OncoGuide.\u003cstrong\u003e \u003c/strong\u003e(C) The number of domestic clinical trials per patient proposed by FoundationOne CDx, GenMineTOP, and NCC OncoGuide. (D) Representative drugs proposed by FoundationOne and GenMineTOP with corresponding frequencies.\u003c/p\u003e","description":"","filename":"Figure9251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/b330494436ebe10486a13444.png"},{"id":100365491,"identity":"d14d288c-5c83-4320-938f-8b8ba8c5af41","added_by":"auto","created_at":"2026-01-16 07:55:15","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":2323506,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of tumor mutational burdens (TMBs) across CGPTs. \u003c/strong\u003e(A) The TMB values of patients in FoundationOne CDx, GenMineTOP, and NCC OncoGuide groups.\u003cstrong\u003e \u003c/strong\u003e(B) Plotting TMB against the number of mutations for each case yields slopes of 1.21, 0.51, and 2.54, with corresponding coefficients of determination (R²) of 0.928, 0.998, and 0.881, respectively.\u003c/p\u003e","description":"","filename":"Figure10251230.png","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/8d4281bd74a1714e1da4e973.png"},{"id":100382238,"identity":"8d123b8a-5679-40d4-bca3-84fe75a53c67","added_by":"auto","created_at":"2026-01-16 10:41:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":40255824,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/559fc338-939b-4321-8725-d21a5452b13c.pdf"},{"id":100365013,"identity":"4c90414a-9840-4cb0-b183-3c01b8832d11","added_by":"auto","created_at":"2026-01-16 07:54:35","extension":"docx","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":173244,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1251203.docx","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/b64b0b8c938b9a689989fbc7.docx"},{"id":100093997,"identity":"b0fb9032-15c8-45e9-ac30-b6044374cd9e","added_by":"auto","created_at":"2026-01-13 01:28:00","extension":"docx","order_by":15,"title":"","display":"","copyAsset":false,"role":"supplement","size":15515,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1251022.docx","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/465b603312c2e076dc946191.docx"},{"id":100366020,"identity":"d9a7d58a-af1b-4dad-83f7-84ea50135ef5","added_by":"auto","created_at":"2026-01-16 07:55:52","extension":"docx","order_by":16,"title":"","display":"","copyAsset":false,"role":"supplement","size":16512,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable2251107.docx","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/5ae8a7d046c4e7ce4b9b69cd.docx"},{"id":100093995,"identity":"5d1d95e3-108f-4ffb-90dc-f507b567e0bf","added_by":"auto","created_at":"2026-01-13 01:28:00","extension":"docx","order_by":17,"title":"","display":"","copyAsset":false,"role":"supplement","size":16943,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable3251203.docx","url":"https://assets-eu.researchsquare.com/files/rs-8480623/v1/61c9023ca8f69c31c6abec21.docx"}],"financialInterests":"","formattedTitle":"Nationwide Genomic Data Analysis of Central Nervous System Tumors in Japan based on C-CAT Database","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAdvancements in molecular genetics of tumorigenesis have underscored the growing significance of molecular classification in cancer diagnosis, treatment selection, and prognostic assessment. Comprehensive genomic profiling test (CGPT), utilizing next-generation sequencing (NGS), enables the analysis of numerous cancer-related genes within a tumor to identify mutations, fusions, copy number variations, and other genomic abnormalities. This approach aims to detect a broad spectrum of genomic changes that may drive tumor development, thereby leading the implementation of personalized therapeutic strategies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn Japan, three CGPTs for tissue specimen are currently covered under the public health insurance system: the FoundationOne\u0026reg; CDx Cancer Genome Profile (FoundationOne CDx) and the OncoGuide\u0026trade; NCC Oncopanel System (NCC OncoGuide) available from 2019, and the GenMineTOP Cancer Genome Profiling System (GenMineTOP) available from 2023. According to the clinical practice guidance for NGS in cancer diagnosis and treatment, edition 2.1 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], CGPT is indicated for patients with solid tumors for which there is no standard treatment or those with solid tumors in whom locally advanced disease or metastasis is seen and who have completed standard treatment (including patients expected to complete the treatment), those who are judged by the attending physician to have a strong likelihood of being suitable for chemotherapy after the test according to the chemotherapy guidelines of the relevant academic society, based on factors such as their general condition and organ function. However, there are no established instruction which CGPT to select, therefore, the choice of CGPT is left to the discretion of the physician.\u003c/p\u003e \u003cp\u003eWhen patients underwent CGPT, their anonymized clinical and genomic data are collected and centralized at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT). This datacenter promotes broad utilization of its aggregated data by hospitals, academic institutions, and industry partners [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While the utility of CGPT in detecting somatic and germline mutations in diffuse gliomas has been previously reported [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], no studies to date have specifically compared the differences in results among the CGPTs in patients with central nervous system (CNS) tumors.\u003c/p\u003e \u003cp\u003eThis study utilized the C-CAT database to examine and compare patient characteristics, genetic mutation profiles, and the corresponding therapeutic recommendations and clinical trials among the three CGPTs available for CNS tumor patients since 2023.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was a nationwide retrospective analysis of patients with CNS tumors in Japan. Genomic and clinical information registered in the C-CAT database between August 2023, when GenMineTOP began its service under insurance coverage, and April 2025 were included. Collected data included patient age, sex, pathological diagnosis, type of genomic panel used, genetic alterations, suggested Pharmaceuticals and Medical Devices Agency (PMDA) and the U.S. Food and Drug Administration (FDA) off-label drugs, proposed domestic clinical trials, and tumor mutation burden (TMB; Mutations/Megabase, Muts/Mb). The pathological diagnoses were obtained directly from the C-CAT database and were not centrally reviewed. Therefore, some diagnoses may not fully reflect the latest WHO classification criteria. For the genetic alterations, only those with evidence level F, defined as \u0026ldquo;known to be involved in oncogenesis\u0026rdquo;, on the C-CAT report were analyzed to minimize the discrepancies for genetic alterations subject to reporting among CGPTs. Mutation data were obtained from the \u0026ldquo;small scale variants\u0026rdquo; category of the C-CAT database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComprehensive genomic profiling tests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMain characteristics of three CGPTs are summarized in Supplementary Table 1. Briefly, FoundationOne CDx was developed by Foundation Medicine (Roche) and approved in Japan in June 2019. It targets 324 DNA alterations in cancer-related genes using NGS. The NCC OncoGuide analyzes 124 DNA alterations using NGS with tumor\u0026ndash;normal paired analysis and is applicable to small samples, including biopsy specimens. Lastly, GenMineTOP, developed and provided by the University of Tokyo and Konica Minolta REALM, Inc., analyzes 737 DNA alterations and 455 RNA alterations via NGS. Unlike FoundationOne CDx, which analyzes tumor tissue only, GenMineTOP performs tumor-normal paired analysis, simultaneously sequencing both tumor tissue and the patient\u0026rsquo;s normal blood sample, allowing for high-confidence distinction between somatic and germline mutations. Additionally, GenMineTOP reports only focal gene amplifications as copy number alterations (CNAs) and does not provide information on gene losses, although the result of focal CNAs are available as graphical supplementary data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComparison of age, the number of genetic alterations detected, the number of drug and clinical trials recommended, and TMB between three groups was evaluated using the Kruskal-Wallis test. The association of the number of somatic mutations and TMB was investigated by simple linear regression model. Statistical analyses were performed using GraphPad Prism 10 (GraphPad Software, Inc., La Jolla, California, USA). Statistical significance was defined as a P-value of \u0026lt;.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll CGPTs were conducted under the national health insurance system. This retrospective study analyzed data originally obtained for clinical purposes. Written informed consent for the use of genomic and clinical information in research was obtained from all participants. The study received approval from the internal review board of the National Cancer Center (approval number: 2020-067) and authorized by the Information Utilization Review Board of C-CAT for secondary data use.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003ePatient demographics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 1,151 CGPTs were performed during the study period. Among them, 563 cases were tested with FoundationOne CDx, 542 with GenMineTOP, and 46 with NCC OncoGuide (Fig 1a). In terms of test distribution, FoundationOne CDx accounted for 77.7% of tests in 2023, while GenMineTOP accounted for 17.5%. However, by 2025, GenMineTOP had increased to 69.3%, while FoundationOne CDx declined to 27.4%, suggesting that GenMineTOP has gained an increasing share of CGPT utilization in Japan over these two years (Fig 1b). The median ages of patients undergoing FoundationOne CDx, GenMineTOP, and NCC OncoGuide testing were 49.0, 49.0, and 44.5 years, respectively, with no significant differences among the groups (Fig 2a). The proportions of male patients were 52.0%, 54.6%, and 47.8% in the FoundationOne CDx, GenMineTOP, and NCC OncoGuide groups, respectively, with no significant difference in sex distribution (p = 0.531; Fig 2b).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcross the entire cohort, glioblastoma (GBM) represented the most frequent pathological diagnosis, comprising 39.44% of cases, followed by astrocytoma (9.64%), diffuse gliomas (8.17%), pilocytic astrocytoma (4.87%), gliomas, glioneuronal and neuronal tumours (4.78%), meningioma (4.78%), adult-type gliomas (2.69%), diffuse midline glioma, H3K27-altered (2.61%), and others (23.02%) (Fig 3). The three predominant diagnoses, GBM, astrocytoma, and diffuse gliomas, were observed at comparable frequencies across all CGPT groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of mutations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median number of mutations with evidence level F detected per patient was 2 with FoundationOne CDx and GenMineTOP, and 1 with NCC OncoGuide, respectively. FoundationOne CDx identified a significantly higher number of mutations compared to the other two CGPTs (p \u0026lt; 0.0001 and p \u0026lt; 0.0001; Fig 4a), and GenMineTOP detected significantly greater number of mutations compared to NCC OncoGuide (p = 0.0003). The most frequently detected mutations in both FoundationOne CDx and GenMineTOP were \u003cem\u003eTP53\u003c/em\u003e, \u003cem\u003eTERT\u003c/em\u003e promoter, \u003cem\u003eNF1, PTEN, EGFR, and IDH1\u003c/em\u003e mutations (Fig 4b).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubanalysis targeting adult GBM (21 years old or older) patients revealed the median number of mutations with the evidence level F detected by Foundation One CDx, GenMineTOP, and NCC OncoGuide per patient was 3, 2, and 1, respectively. There was no significant difference between FoundationOne CDx and GenMineTOP (p = 0.29; Supp Fig 1a), but NCC OncoGuide detected significantly smaller number of mutations compared to Foundation One (p = 0.0041), and GenMineTOP (p = 0.0028). The most frequently detected mutations were \u003cem\u003eTERT\u003c/em\u003e, \u003cem\u003eTP53, PTEN, EGFR, and NF1,\u003c/em\u003e which were commonly identified by both FoundationOne and GenMineTOP (Supp Fig 1b).\u003c/p\u003e\n\u003cp\u003eThe median number of detected focal CNAs per patient was 2 for FoundationOne CDx, and 0 for GenMineTOP and NCC OncoGuide. FoundationOne CDx again detected a significantly higher number of focal CNAs compared to the other two tests (p \u0026lt; 0.0001 for both comparisons; Fig 5a). While the most frequently detected CNAs in FoundationOne CDx were \u003cem\u003eCDKN2A\u003c/em\u003e loss and \u003cem\u003eCDKN2B\u003c/em\u003e loss, these deletions were not reported in GenMineTOP (Fig 5b). As previously noted, GenMineTOP does not report gene deletions such as \u003cem\u003eCDKN2A/B\u003c/em\u003e loss or \u003cem\u003ePTEN\u003c/em\u003e loss. However, in one case from our institution involving a 46-year-old female patient with astrocytoma, IDH-mutant, CNS WHO grade 4, the supplementary information in the GenMineTOP report did indicate a \u003cem\u003eCDKN2A/B\u003c/em\u003e homozygous deletion, even though it was not explicitly stated in the supplementary report. This deletion was further confirmed by our in-house targeted sequencing. Additionally, broad CNAs such as chromosome 10 loss in a 51-year-old male patient with molecular GBM, and 1p/19q codeletion in a 28-year-old male patient with oligodendroglioma, CNS WHO grade 3, were indicated in the supplementary information in the GenMineTOP report (Fig 6).\u003c/p\u003e\n\u003cp\u003eRegarding gene fusions, the detection frequencies were 7.5% for FoundationOne CDx, 9.6% for GenMineTOP, and 8.7% for NCC OncoGuide (Fig 7a). The most commonly identified fusions across the three CGPTs were \u003cem\u003eKIAA1549\u0026ndash;BRAF\u003c/em\u003e and \u003cem\u003eFGFR3\u0026ndash;TACC3\u003c/em\u003e. In addition to these, GenMineTOP detected glioma related gene fusions such as \u003cem\u003eEGFR\u0026ndash;SEPT14\u003c/em\u003e and \u003cem\u003ePTPRZ1\u0026ndash;MET\u003c/em\u003e compared with FoundationOne CDx (Fig 7b). It is important to note that FoundationOne CDx, which reports gene fusions based solely on DNA sequencing without considering the direction of transcription, has frequently reported bidirectional configurations such as \u003cem\u003eKIAA1549\u0026ndash;BRAF\u0026nbsp;\u003c/em\u003eand\u003cem\u003e\u0026nbsp;BRAF\u0026ndash;KIAA1549\u003c/em\u003e in the same case, likely leading to the inadvertent inclusion of non-oncogenic configurations like \u003cem\u003eBRAF\u0026ndash;KIAA1549\u003c/em\u003e. In contrast, GenMineTOP consistently reported a single, correctly oriented fusion configuration, directly validated by RNA sequencing, which enables the accurate determination of the transcription direction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGermline mutations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 542 GenMineTOP cases, 27 germline mutations were identified in 25 patients (4.6%). The most frequently detected germline mutation was \u003cem\u003eTP53\u003c/em\u003e (n = 9, 1.66%), followed by \u003cem\u003eBRCA2\u003c/em\u003e (n = 3, 0.55%), and \u003cem\u003eMSH6\u003c/em\u003e (n = 3, 0.55%, Fig 8).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProposed drugs and clinical trials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median number of proposed drugs and clinical trials per patient varied across the three CGPT platforms. For PMDA off-label drugs, the medians were 2 for FoundationOne CDx, 1 for GenMineTOP and NCC OncoGuide (Fig 9a). For FDA off-label drugs, the medians were 3, 2, and 2, respectively (Fig 9b). Patients in the FoundationOne CDx group received significantly more proposals for PMDA and FDA off-label drugs compared to those in the GenMineTOP group (p = 0.0006, p = 0.0002). The median number of proposed domestic clinical trials was 2 for FoundationOne CDx, 1 for GenMineTOP and NCC OncoGuide. Patients in the FoundationOne CDx group received significantly more domestic clinical trial suggestions than those in the GenMineTOP group (p \u0026lt; 0.0001) and NCC OncoGuide (p = 0.04, Fig 9c).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe proposed drugs were further evaluated. The frequently proposed drugs \u0026nbsp;were everolimus (24.3%), temsirolimus (20.8%), pazopanib hydrochloride (19.5%), lenvatinib (14.6%), cabozantinib (14.0%), capivasertib and fulvestrant (13.3%), sorafenib (12.3%), doxorubicin hydrochloride (11.6%), imatinib mesylate (10.8%), and panitumumab (9.6%) in FoundationOne CDx and capivasertib and fulvestrant (14.2%), Lenvatinib (14.0%), sorafenib (13.8%), everolimus (13.7%), temsirolimus (13.3%), pazopanib hydrochloride (13.1%), selumetinib (12.5%), panitumumab (11.8%), cabozantinib\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;(10.3%), temozolomide + vandetanib (9.2%) in GenMineTOP (Fig 9d and supplementary table 2). When we examined the representative drugs proposed and the gene alterations on which their recommendations were based, a considerable number of cases showed \u003cem\u003ePTEN\u003c/em\u003e loss. As mentioned above, this alteration was identified only by FoundationOne, which likely explains the significantly higher number of drug recommendations generated by FoundationOne compared to GenMineTOP (Supplementary table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTumor mutation burden\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median values of TMB were 2.0, 2.1, and 2.3 Muts/Mb for FoundationOne CDx, GenMineTOP, and NCC OncoGuide, respectively (Fig 10a), with no statistically significant differences among the three panels. Plotting TMB against the number of mutations for each case yielded slopes of 1.21, 0.51, and 2.54, with corresponding coefficients of determination (R\u0026sup2;) of 0.928, 0.998, and 0.881, respectively (Fig 10b).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eAnalysis of C-CAT data revealed a growing number of GenMineTOP cases for CNS tumors following its inclusion in public health insurance coverage in 2023. Two primary factors may account for the expanding market share of GenMineTOP within Japan\u0026rsquo;s CGP landscape. First, as a domestically developed CGPT, GenMineTOP enables genomic and clinical data to be analyzed and managed entirely in the home country, thereby minimizing the risk of data being transferred overseas. Second, GenMineTOP was designed to detect a wider range of genetic alterations in both DNA and RNA compared to the other two CGPTs, with the expectation of yielding more comprehensive and clinically actionable information. While the first rationale appears valid, the second was unfortunately not supported by the findings of this study. Despite initial expectations, our results did not demonstrate a significant advantage for GenMineTOP in terms of either the number or clinical relevance of the detected alterations.\u003c/p\u003e \u003cp\u003eOur results showed that FoundationOne CDx detected significantly more CNA compared to GenMineTOP and NCC OncoGuide. A notable limitation of GenMineTOP is that it reports only gene amplifications and therefore does not capture gene loss events. This difference may have contributed to the result that FoundationOne CDx could proposed a significantly greater number of PMDA off-label drugs and domestic clinical trials. Furthermore, given that such deletions, particularly \u003cem\u003eCDKN2A/B\u003c/em\u003e homozygous deletions, are critical for the molecular diagnosis of CNS tumors, the absence of this information in the GenMineTOP report, despite being available in supplementary information, represents a significant shortcoming that requires prompt rectification.\u003c/p\u003e \u003cp\u003eIn addition to CNAs, FoundationOne CDx also detected significantly more mutations compared to the other two CGPT. The reasons underlying the discrepancies in detection rates among the three CGPT remain unclear. Since, as of July 2023, reimbursement for CGPT is limited to one test per patient over their lifetime, patients are unable to undergo both FoundationOne CDx and GenMineTOP. Therefore, further academic investigation is urgently needed to clarify the differences in detection capabilities among CGPTs and to guide optimal test selection.\u003c/p\u003e \u003cp\u003eIn contrast, GenMineTOP is capable of detecting gene fusions with proper orientation, including \u003cem\u003eKIAA1549-BRAF\u003c/em\u003e, \u003cem\u003eFGFR3-TACC3\u003c/em\u003e, \u003cem\u003eEGFR-SEPT14\u003c/em\u003e, and \u003cem\u003ePTPRZ1-MET\u003c/em\u003e. \u003cem\u003eKIAA1549-BRAF\u003c/em\u003e fusion is found in 77.3\u0026ndash;78.7% of pilocytic astrocytoma [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and known as a molecular profile characteristically altered [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Only the \u003cem\u003eKIAA1549-BRAF\u003c/em\u003e fusion is oncogenic, and therefore its configuration is critically important. In this regard, GenMineTOP, which determines the precise configuration of gene fusions through RNA sequencing, is considered superior to FoundationOne CDx. \u003cem\u003eFGFR3-TACC3\u003c/em\u003e and \u003cem\u003eEGFR-SEPT14\u003c/em\u003e, are gene fusions commonly found in GBM with frequencies of 4.1% [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and 4% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, although not explicitly stated in the report, the supplementary data of GenMineTOP demonstrate key chromosomal alterations, including 1p/19q codeletion characteristic of oligodendroglioma and whole chromosome 7 gain with chromosome 10 loss, which define molecular GBM. These alterations are essential for accurate tumor classification, and omission of such information may lead to under-diagnosis.\u003c/p\u003e \u003cp\u003eIn this study, the frequency of germline mutations with evidence level F among patients with CNS tumors was found to be 4.6%, which is lower than the previously reported frequencies of 7.7% in patients with diffuse gliomas [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and 6.2% in patients with malignant solid tumors in Japan [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This lower frequency is likely because C-CAT designates evidence F only to germline mutations listed in the American College of Medical Genetics and Genomics (ACMG) statement [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], thereby excluding germline mutations not included on the ACMG statements, such as \u003cem\u003eNF1\u003c/em\u003e and \u003cem\u003ePOLE\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eThe observed difference in the slope of the plotted relationship between TMB and somatic mutations in FoundationOne CDx and GenMineTOP can be attributed to differences in the definition of TMB between the two CGP platforms. According to the official documentation of FoundationOne CDx, TMB is defined as \u0026ldquo;the number of synonymous and nonsynonymous mutations with an allele frequency of 5% or higher.\u0026rdquo; In contrast, GenMineTOP defines TMB as \u0026ldquo;the number of nonsynonymous mutations with an allele frequency of 5% or higher and a read depth of at least 100.\u0026rdquo; Synonymous mutations are nucleotide substitutions that do not alter the resulting amino acid sequence, whereas nonsynonymous mutations lead to an amino acid change. The inclusion of synonymous mutations in FoundationOne CDx, but not in GenMineTOP, likely accounts for the discrepancy in TMB values and their relationship with the number of detected somatic mutations.\u003c/p\u003e \u003cp\u003eOne limitation of this study was that this study did not involve direct matched case comparisons among the three CGPTs. As such, differences in the detection of genetic alterations or therapeutic suggestions may be influenced by variations in patient backgrounds or tumor characteristics, rather than intrinsic differences in assay performance. Also, the retrospective nature of the study, relying on real-world registry data, may introduce selection bias or inconsistencies in data quality. Furthermore, differences in clinical practice patterns among institutions could have influenced CGPT selection and reporting. Lastly, the analysis was based on the C-CAT database summary reports, without access to raw sequencing data. Therefore, it was not possible to verify or reanalyze variant calls, especially in borderline or discordant cases.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eFoundationOne exhibits greater number of mutations, CNAs, and generating therapeutic suggestions, while GenMineTOP excels in identifying fusion genes and germline variants. These findings underscore that each CGPT possesses distinct analytical strengths, and the choice of platform may influence the genomic landscape and therapeutic opportunities identified in CNS tumor patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets used and/or analyzed during this study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any specific grants or financial support from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eThe study received approval from the internal review board of the National Cancer Center (approval number: 2020-067) and authorized by the Information Utilization Review Board of C-CAT for secondary data use.\u003c/li\u003e\n \u003cli\u003eInformed Consent: Written informed consent for the use of genomic and clinical data for research purposes. The tests were performed under regular medical insurance.\u003c/li\u003e\n \u003cli\u003eRegistry and the Registration No. of the study/trial: N/A.\u003c/li\u003e\n \u003cli\u003eAnimal Studies: N/A.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePankiw M, Brezden-Masley C, Charames GS (2023) Comprehensive genomic profiling for oncological advancements by precision medicine. Med Oncol 41 (1):1. doi:10.1007/s12032-023-02228-x\u003c/li\u003e\n\u003cli\u003eNaito Y, Aburatani H, Amano T, Baba E, Furukawa T, Hayashida T, Hiyama E, Ikeda S, Kanai M, Kato M, Kinoshita I, Kiyota N, Kohno T, Kohsaka S, Komine K, Matsumura I, Miura Y, Nakamura Y, Natsume A, Nishio K, Oda K, Oda N, Okita N, Oseto K, Sunami K, Takahashi H, Takeda M, Tashiro S, Toyooka S, Ueno H, Yachida S, Yoshino T, Tsuchihara K, Japanese Society of Medical O, Japan Society of Clinical O, Japanese Cancer A (2021) Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (edition 2.1). Int J Clin Oncol 26 (2):233-283. doi:10.1007/s10147-020-01831-6\u003c/li\u003e\n\u003cli\u003eKohno T, Kato M, Kohsaka S, Sudo T, Tamai I, Shiraishi Y, Okuma Y, Ogasawara D, Suzuki T, Yoshida T, Mano H (2022) C-CAT: The National Datacenter for Cancer Genomic Medicine in Japan. Cancer Discov 12 (11):2509-2515. doi:10.1158/2159-8290.CD-22-0417\u003c/li\u003e\n\u003cli\u003eOmura T, Takahashi M, Ohno M, Miyakita Y, Yanagisawa S, Tamura Y, Kikuchi M, Kawauchi D, Nakano T, Hosoya T, Igaki H, Satomi K, Yoshida A, Sunami K, Hirata M, Shimoi T, Sudo K, Okuma HS, Yonemori K, Suzuki H, Ichimura K, Narita Y (2022) Clinical Application of Comprehensive Genomic Profiling Tests for Diffuse Gliomas. Cancers (Basel) 14 (10). doi:10.3390/cancers14102454\u003c/li\u003e\n\u003cli\u003eSievert AJ, Jackson EM, Gai X, Hakonarson H, Judkins AR, Resnick AC, Sutton LN, Storm PB, Shaikh TH, Biegel JA (2009) Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol 19 (3):449-458. doi:10.1111/j.1750-3639.2008.00225.x\u003c/li\u003e\n\u003cli\u003eColin C, Padovani L, Chappe C, Mercurio S, Scavarda D, Loundou A, Frassineti F, Andre N, Bouvier C, Korshunov A, Lena G, Figarella-Branger D (2013) Outcome analysis of childhood pilocytic astrocytomas: a retrospective study of 148 cases at a single institution. Neuropathol Appl Neurobiol 39 (6):693-705. doi:10.1111/nan.12013\u003c/li\u003e\n\u003cli\u003eJones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21):8673-8677. doi:10.1158/0008-5472.CAN-08-2097\u003c/li\u003e\n\u003cli\u003eLouis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23 (8):1231-1251. doi:10.1093/neuonc/noab106\u003c/li\u003e\n\u003cli\u003eMata DA, Benhamida JK, Lin AL, Vanderbilt CM, Yang SR, Villafania LB, Ferguson DC, Jonsson P, Miller AM, Tabar V, Brennan CW, Moss NS, Sill M, Benayed R, Mellinghoff IK, Rosenblum MK, Arcila ME, Ladanyi M, Bale TA (2020) Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions. Acta Neuropathol Commun 8 (1):186. doi:10.1186/s40478-020-01058-6\u003c/li\u003e\n\u003cli\u003eFrattini V, Trifonov V, Chan JM, Castano A, Lia M, Abate F, Keir ST, Ji AX, Zoppoli P, Niola F, Danussi C, Dolgalev I, Porrati P, Pellegatta S, Heguy A, Gupta G, Pisapia DJ, Canoll P, Bruce JN, McLendon RE, Yan H, Aldape K, Finocchiaro G, Mikkelsen T, Prive GG, Bigner DD, Lasorella A, Rabadan R, Iavarone A (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45 (10):1141-1149. doi:10.1038/ng.2734\u003c/li\u003e\n\u003cli\u003eYamaguchi T, Ikegami M, Aruga T, Kanemasa Y, Horiguchi SI, Kawai K, Takao M, Yamada T, Ishida H (2024) Genomic landscape of comprehensive genomic profiling in patients with malignant solid tumors in Japan. Int J Clin Oncol 29 (10):1417-1431. doi:10.1007/s10147-024-02554-8\u003c/li\u003e\n\u003cli\u003eLee K, Abul-Husn NS, Amendola LM, Brothers KB, Chung WK, Gollob MH, Gordon AS, Harrison SM, Hershberger RE, Li M, Ondrasik D, Richards CS, Stergachis A, Stewart DR, Martin CL, Miller DT, [email protected] ASFWGEa (2025) ACMG SF v3.3 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med 27 (8):101454. doi:10.1016/j.gim.2025.101454\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Comprehensive genomic profiling test, Foundation One, GenMineTOP, NCC OncoGuide","lastPublishedDoi":"10.21203/rs.3.rs-8480623/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8480623/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eComprehensive genomic profiling test (CGPT) using next-generation sequencing (NGS) plays a vital role in cancer diagnosis, treatment option, and prognostic evaluation. In Japan, three tissue-based CGPTs, FoundationOne\u0026reg; CDx, GenMineTOP, and NCC OncoGuide\u0026trade;, are reimbursed under public health insurance. However, their comparative performance in central nervous system (CNS) tumors remains unclear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a nationwide, retrospective analysis using data from the Center for Cancer Genomics and Advanced Therapeutics database. A total of 1,151 patients with CNS tumors who underwent CGPT between August 2023 and April 2025 were included. Patient characteristics, genetic mutations, tumor mutation burden, and numbers of drug and clinical trial suggestions were compared across the three CGPTs.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFoundationOne\u0026reg; CDx detected significantly more mutations and copy number alterations than GenMineTOP and NCC OncoGuide. It also proposed more off-label drugs and domestic clinical trials. Conversely, GenMineTOP demonstrated the highest detection rate of gene fusions (9.6%), including KIAA1549-BRAF, FGFR3-TACC3, and EGFR-SEPT14, and PTPRZ1-MET. Furthermore, GenMineTOP identified germline mutations in 4.6% of patients, commonly involving TP53, BRCA2, and MSH6.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFoundationOne\u0026reg; CDx exhibits greater number of mutations, copy number alterations, and generating therapeutic suggestions, while GenMineTOP excels in identifying fusion genes and germline variants. These findings underscore that each CGPT possesses distinct analytical strengths, and the choice of platform may influence the genomic landscape and therapeutic opportunities identified in CNS tumor patients.\u003c/p\u003e","manuscriptTitle":"Nationwide Genomic Data Analysis of Central Nervous System Tumors in Japan based on C-CAT Database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 01:27:51","doi":"10.21203/rs.3.rs-8480623/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2026-02-21T01:05:08+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-01-06T14:50:37+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-06T12:55:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-04T10:28:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-12-30T06:09:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c3d13bdf-4074-48fd-b20f-6eecd8789f81","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-02T14:03:42+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-13 01:27:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8480623","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8480623","identity":"rs-8480623","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}