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Patients with advanced cancer undergo comprehensive genomic profiling in Japan only after treatment options have been exhausted. Patients with a very poor prognosis were not able to undergo profiling tests, resulting in a selection bias called length bias, which makes accurate survival analysis impossible. The actual impact of length bias on the overall survival of patients who have undergone profiling tests is unclear, yet appropriate methods for adjusting for length bias have not been developed. To assess the length bias in overall survival, we established a simulation‐based model for length bias adjustment. This study utilized clinicogenomic data of 8813 patients with advanced cancer who underwent profiling tests at hospitals throughout Japan between June 2019 and April 2022. Length bias was estimated by the conditional Kendall τ statistics and was significantly positive for 13 of the 15 cancer subtypes, suggesting a worse prognosis for patients who underwent profiling tests in early timing. The median overall survival time in colorectal, breast, and pancreatic cancer from the initial survival‐prolonging chemotherapy with adjustment for length bias was 937 (886–991), 1225 (1152–1368), and 585 (553–617) days, respectively (median; 95% credible interval). Adjusting for length bias made it possible to analyze the prognostic relevance of oncogenic mutations and treatments. In total, 12 tumor‐specific oncogenic mutations correlating with poor survival were detected after adjustment. There was no difference in survival between FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) or gemcitabine with nab‐paclitaxel‐treated groups as first‐line chemotherapy for pancreatic cancer. Adjusting for length bias is an essential part of utilizing real‐world clinicogenomic data. Length bias due to delayed enrollment in comprehensive genomic profiling tests makes accurate survival analysis impossible. This study enrolling 8813 Japanese patients with advanced cancer who underwent a profiling test showed a worse prognosis for patients who underwent profiling tests in early timing. Our adjusting method for length bias made it possible to analyze overall survival and the prognostic impact of oncogenic mutations and treatments.

Purpose Leptomeningeal metastasis (LM) is a complication of surgery for brain metastasis and is a risk factor of poor prognosis. The risk of LM is particularly high after surgery for a breast cancer metastasis to the brain. If the risk of LM after surgical resection for a brain metastasis were predictable, appropriate adjuvant therapy could be administered to individual patients to improve their prognosis. The present study aimed to reveal the genetic characteristics of brain metastases as means of predicting LM in breast cancer patients. Methods Ten patients with brain metastases of breast cancer presented LM after surgical resection were analyzed by whole-exome sequencing. Results A chromodomain-helicase-DNA-binding protein 5 (CHD5) gene alteration was detected in nine cases (90%), including a nonsynonymous variant in four cases and copy number deletion in five cases. CHD5 protein expression was lost in nine cases and had decreased in one case. The frequency of CHD5 gene alteration in brain metastases with LM was significantly higher than in primary breast cancer (2.3%) or in brain metastases of breast cancer (0%) (p < 0.0001). Conclusions These results suggested that the CHD5 gene alteration was associated with LM after surgical resection of breast cancer brain metastases. Searching for the gene alteration might predict the LM risk after surgical resection.

Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array ( n  = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 ( n  = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation ( n  = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation ( n  = 9), PPM1D mutation ( n  = 2), and a novel type of PPM1D fusion ( n  = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the “RTK I (PDGFRA)” group, and those DCGs had a gene expression signature that was highly associated with PDGFRA . Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10 , a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3 , which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.

PurposeWe previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. The aim of this study was to further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their relatively benign clinical behavior.MethodsWe compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis.ResultsBy comparing expression levels of genes of 19q-loss astrocytomas to those of 19q-intact astrocytomas, 102 up-regulated genes and 162 down-regulated genes were extracted. The down-regulated genes clustered heavily to 19q and 4p while the up-regulated genes clustered to 4q. It was noteworthy that fibroblast growth factor 1 associated with stem cell maintenance and multiple genes associated with glioma progression were down-regulated in 19q-loss astrocytomas, and these results were validated with the independent TCGA data set. On t-SNE analysis of the 19q-loss astrocytomas with other IDH-mutant glioma subgroups from the TCGA datasets, the expression pattern of the 19q-loss astrocytomas showed no shift toward oligodendrogliomas with 1p/19q codeletion but rather constituted a subgroup of astrocytoma.ConclusionsThese findings suggested that 19q-loss in astrocytomas is more likely acquired event rather than an early event in oncogenesis like the 1p/19q-codeletion in oligodendrogliomas, and that the biological features of 19q-loss astrocytomas are possibly related to differentially expressed genes associated with stem cell maintenance and glioma progression.

IDH‐mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II‐IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next‐generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH‐mutated gliomas, 12 were 1p‐intact/19q‐intact (anaplastic astrocytomas [AA]), 7 were 1p‐intact/19q‐loss (AA), and 23 showed 1p/19q‐codeletion (anaplastic oligodendrogliomas). Of the 88 IDH‐wild type glioblastomas (GBMs), 14 showed 1p‐intact/19q‐loss status. All of the seven 1p‐intact/19q‐loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q‐loss AAs had regions presenting oligodendroglioma‐like morphology, and were associated with significantly longer overall survival compared to 19q‐intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q‐loss GBM and 19q‐intact GBM (P = .4). In a case of 19q‐loss AA, both oligodendroglial morphology and 19q‐loss disappeared after recurrence, possibly indicating correlation between 19q‐loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH‐mutated astrocytomas harboring 19q‐loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q‐intact astrocytomas. Even after the introduction of the WHO 2016 classification, heterogeneity within each category still exists, and the next challenges would include whether we can further refine subtyping of gliomas. Our analysis of 170 diffuse gliomas suggested that there appeared to be a subgroup of IDH‐mutated astrocytomas characterized by isolated 19q‐loss, oligodendroglial morphology and significantly better prognosis compared to other 19q‐intact astrocytomas, providing with a new genetic‐morphological‐clinical association that may characterize a small but distinct subtype within anaplastic astrocytoma.

IntroductionThe introduction of systemic chemotherapy for advanced hepatocellular carcinoma in recent years has led to the prediction that cases of brain metastases from hepatocellular carcinoma will increase. However, because brain metastases from hepatocellular carcinoma are relatively rare, the characteristics of this pathology are poorly understood.MethodsWe carried out a multicenter retrospective study to verify the characteristics of brain metastases from hepatocellular carcinoma in Japan.ResultsA total of 38 patients were enrolled and patient characteristics were poor general condition in many patients due to the progression of primary cancers. Stereotactic radiosurgery/stereotactic radiotherapy alone was the most common treatment (39.5%), with best supportive care provided for 10.5%. Median survival was 6 months, the neurological death rate was 28%, and the rate of brain hemorrhage was high (39.5%). Overall survival was analyzed for correlations with age, etiology of chronic liver disease, albumin–bilirubin (ALBI) grade, RPA classification, control of the primary tumor, number of brain metastases, brain hemorrhage, surgical resection, and radiotherapy. In multivariate analysis, ALBI grade, number of brain metastases and brain hemorrhage showed statistically significant correlation.ConclusionsA multivariate analysis extracted three items—ALBI grade, number of brain metastases, and brain hemorrhage—as prognostic factors for survival of brain metastases from hepatocellular carcinoma.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.

Abstract A 46-year-old female patient with glioblastoma multiforme (GBM), IDH wild type developed severe pancytopenia 5 months after postoperative chemoradiotherapy. Bone marrow aspirate showed normocellular marrow with 70.0% abnormal cells, which suggested the possibility of acute myeloid leukemia. Immunophenotypic analysis did not show any hematological lineage markers, except for cluster of differentiation 56. The results of immunohistochemical staining of glial fibrillary acidic protein and oligodendrocyte transcription Factor 2 were positive. Based on these findings, the patient was diagnosed with bone marrow metastasis from GBM. Bone marrow metastasis from GBM is rare and little is known about the morphological characteristics of bone marrow aspiration smear findings. We experienced a rare case with marrow metastasis from GBM mimicking acute myeloid leukemia.