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.
Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.
The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response.We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS).The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27-1.62), SC (HR = 2.00, 95% CI = 1.76-2.28), or SCC (HR = 4.23, 95% CI = 3.34-5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56-0.80), MSEC (HR = 0.58, 95% CI = 0.49-0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40-0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74-1.28).The proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.
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.
// Rui-qi Zhang 1, 2, 4, * , Zhifeng Shi 4, * , Hong Chen 5 , Nellie Yuk-Fei Chung 1, 2 , Zi Yin 1, 2 , Kay Ka-Wai Li 1, 2 , Danny Tat-Ming Chan 3 , Wai Sang Poon 3 , Jinsong Wu 4 , Liangfu Zhou 4 , Aden Ka-yin Chan 1, 2 , Ying Mao 4 , Ho-Keung Ng 1, 2 1 Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China 2 Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong, China 3 Neurosurgery Division, Department of Surgery, Chinese University of Hong Kong, Hong Kong, China 4 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China 5 Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Aden Ka-yin Chan, e-mail: adenchan@cuhk.edu. hk Ying Mao, e-mail: yingmao168@hotmail.com Ho-Keung Ng, e-mail: hkng@cuhk.edu.hk Keywords: glioblastoma, IDH1, BRAF, H3F3A, prognostication Received: June 14, 2015 Accepted: September 25, 2015 Published: October 05, 2015 ABSTRACT While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF , H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF -V600E (15%), H3F3A -K27M (15.9%), H3F3A -G34R/V (2.8%) and IDH1 -R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERT p mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF -V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A -K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1 -R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF , H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF , H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas.
Supplementary Methods, Figures 1-3 from c-Jun Protects Hypoxia-Inducible Factor-1α from Degradation via Its Oxygen-Dependent Degradation Domain in a Nontranscriptional Manner
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.
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