Abstract Oligodendroglioma is a subtype of diffuse glioma defined by a mutation in the isocitrate dehydrogenase (IDH) genes and a co-deletion of chromosome arms 1p and 19q. These tumors primarily occur in adult patients in their third and fourth decade of life and are universally fatal due to an inevitable recurrence that follows a treatment regimen of surgical resection and an optional combination of alkylating chemotherapy and/or radiation therapy. While initially slow growing, recurrent tumors exhibit increasingly aggressive phenotypes that become progressively more difficult to treat with conventional therapy. Currently, the molecular mechanisms and cellular phenotypes that drive this recurrence remain unknown. To understand these factors, we assembled a cohort of matched initial and recurrent oligodendroglioma samples from over 100 patients and performed whole-genome sequencing and whole-exome sequencing on each of them. To link these molecular profiles to cell state changes, we additionally performed bulk and single-nucleus RNA-sequencing on a subset of these tumor pairs. In nearly 40% of alkylating chemotherapy-treated patients, recurrent tumors presented with hypermutation that corresponded with an increase in neoplastic cell proliferation. Additionally, while individual somatic alterations specific to recurrence were relatively rare, we observed a subset of tumors that acquired deletions in the cell cycle regulator CDKN2A following treatment with radiotherapy. Acquisition of either of these features associated with shorter patient survival and higher grade at recurrence, implicating cell cycle dysregulation as a mechanism of treatment resistance and increased tumor severity. Together, these results indicate that oligodendrogliomas evolve in a treatment-specific manner following chemo- and radiation therapy and highlight key pathways that can be targeted to delay the onset of recurrence.
IDH wild-type astrocytoma is described as a provisional entity within the new WHO classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be sub-stratified prognostically. 718 adult WHO Grade II and III gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. 166 IDH wild-type cases were identified for further studies and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter and BRAF were examined. EGFR amplification, BRAF and H3F3A mutations were observed in 13.3%, 8.6% and 9.1% respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.4% of cases. Favorable outcome was observed in tumors with oligodendroglial phenotype, grade II histology and total resection. Independent adverse prognostic values of older age, non-total resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariate analysis. Tumors were further classified into “molecularly” high grade (harboring EGFR, H3F3A or TERTp) (median OS=1.2 years) and lower-grade (lacking all of the three) (median OS=7.6 years) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. In summary, adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers including MYB, EGFR, TERTp and H3F3A should be examined to delineate bad and good prognostic groups.
The incidence of Alzheimer's disease has been suggested to be low in Chinese but there have been few histological studies of the disease and of Alzheimer-related changes in Chinese. In this study, brains from 8 cases of Alzheimer's disease and 27 non-demented elderly Chinese individuals were examined comprehensively. Dementia was excluded in the latter by careful retrospective interviews with relatives. Histological sections were taken from standardised areas and quantitative analysis of neuritic plaques, neurofibrillary tangles and diffuse plaques was carried out with 3 histological methods: microwave modification of Bielschowsky, Bodian and beta A4 protein immunostaining. There were conspicuous differences in the amounts of neurofibrillary tangles and neuritic plaques seen between the demented and non-demented groups. In the latter, the amount of Alzheimer-related changes appeared to be much smaller than in corresponding studies among Western populations. Diffuse plaques were not found to be a good histological marker for dementia.
Abstract Genome-wide DNA methylation profiling has emerged as an important diagnostic tool that complements histopathology for CNS tumors in children and adults. Literature describing its application in Asian countries is nonetheless limited. Herein, we report the feasibility and utility of adopting such platform for children diagnosed with CNS tumors in Hong Kong. A multi-institutional cohort (n=94, 97% of Chinese ethnicity) with CNS embryonal or high grade neuroepithelial tumors (HGNET) diagnosed in Hong Kong from 1996–2020 was assembled based on tissue availability. DNA was extracted from FFPE tumor material (median 301ng, range 13-1000ng), bisulfite converted and profiled with the Infinium Methylation EPIC BeadChip kit. Raw data were analyzed on the German Cancer Research Center MNP 2.0 classifier and through unsupervised dimensionality-reduction analysis (t-SNE) referencing a published CNS tumor reference dataset (GSE90496). The radio-histologic diagnosis included medulloblastoma (n=65), ATRT (n=9), pineal parenchymal tumors (n=7), ETMR (n=5), CNS-PNET (n=4) and other embryonal tumors/HGNETs (n=4). Methylation class could be assigned based on results from MNP 2.0 (calibrated score ≥ 0.9) in 62 patients (66%, including 2 clustering with control) and t-SNE in 22 (23%), while no-match was encountered in 10 (11%). Methylation-based analysis allowed confirmation of diagnosis and assignment of molecular subgroup in 64 patients (68%), confirmation of histologic diagnosis alone in 5 (5%) and resulted in revision/reassignment of diagnosis in 13 (14%). Among medulloblastoma samples that were assigned molecular tumor classes (n=57), 8 clustered with WNT-activated medulloblastoma, 13 with SHH-activated medulloblastoma, 10 with Group 3 medulloblastoma, 21 with Group 4 medulloblastoma, and 5 with non-medulloblastoma entities (high-grade gliomas=3, ETMR=1, ATRT=1). In conclusion, epigenomic profiling allowed refinement of disease classification for pediatric CNS tumors. Availability of such methodology in Asia sets the stage for international collaborations in molecularly-driven trials.
Supplementary Figure 6 from Sirtuin 1 Is Upregulated in a Subset of Hepatocellular Carcinomas where It Is Essential for Telomere Maintenance and Tumor Cell Growth
Supplementary Table 1 from Sirtuin 1 Is Upregulated in a Subset of Hepatocellular Carcinomas where It Is Essential for Telomere Maintenance and Tumor Cell Growth
The presence of human herpesvirus 6 (HHV-6) in brain tissues of 40 consecutive post-mortem cases was examined. For each case, autopsy samples were collected from the cerebellum, frontal, temporal, parietal and occipital lobes of both sides of the brain. HHV-6 DNA was detected by nested polymerase chain reaction and characterised into variants A and B. Overall, 97/400 (24.3%) samples were positive for HHV-6 DNA with 16 being variant A and 81 being variant B, but none of the samples harboured both variants. When analysed by patient, 34/40 (85%) had HHV-6 DNA detected in the brain. The viral DNA positivity did not show significant variation with gender and age. Four patients harboured variant A, 23 harboured variant B, and seven had both variants at different positions. The results indicate that both HHV-6A and HHV-6B are neurotropic and human brain may be another site for latency. HHV-6B was detected in brain tissues of a majority (75%) of the studied population and with a widespread distribution within the brain. Although the observed prevalence of HHV-6A in brain is lower (27.5%), in view of its lower seroprevalence, the neuroinvasive potential of variant A may be comparable to that of variant B. Although both variants are potential pathogens for the nervous system, the fact that they can exist, probably for most of the time, as commensals in human brain needs to be considered when interpreting their roles in neuropathology.
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