Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced somatic mutation rates in survival outliers of glioblastoma

The study of survival outliers of glioblastoma can provide important clues on gliomagenesis as well as on the ways to alter clinical course of this almost uniformly lethal cancer type. However, there has been little consensus on genetic and epigenetic signatures of the long-term survival outliers of glioblastoma. Although the two classical molecular markers of glioblastoma including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are associated with overall survival rate of glioblastoma patients, they are not specific to the survival outliers. In this study, we compared the two groups of survival outliers of glioblastoma with IDH wild-type, consisting of the glioblastoma patients who lived longer than 3 years (n = 17) and the patients who lived less than 1 year (n = 12) in terms of genome-wide DNA methylation profile. Statistical analyses were performed to identify differentially methylated sites between the two groups. Functional implication of DNA methylation patterns specific to long-term survivors of glioblastoma were investigated by comprehensive enrichment analyses with genomic and epigenomic features. We found that the genome of long-term survivors of glioblastoma is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. In the long-term survival glioblastoma-specific sites distant from CGI, somatic mutations of glioblastoma are enriched with higher DNA methylation, suggesting that the hypomethylation in long-term survival glioblastoma can contribute to reduce the rate of somatic mutation. On the other hand, the hypermethylation near CGIs associates with transcriptional downregulation of genes involved in cancer progression pathways. Using independent cohorts of IDH1/2- wild type glioblastoma, we also showed that these two patterns of DNA methylation can be used as molecular markers of long-term survival glioblastoma. Our results provide extended understanding of DNA methylation, especially of DNA hypomethylation, in cancer genome and reveal clinical importance of DNA methylation pattern as prognostic markers of glioblastoma.This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (NRF-2018M3A9H3021707). in Korea, and the Seoul National University Hospital Research Fund (3020180010)

Role of plasma EBV DNA levels in predicting recurrence of nasopharyngeal carcinoma in a western population

<p>Abstract</p> <p>Background</p> <p>Loco-regionally advanced nasopharyngeal carcinomas can be cured by the combination of chemotherapy and radiotherapy. In Eastern countries, plasma levels of viral Epstein-Barr deoxyribonucleic acid (DNA) are accurate in predicting recurrence, but few data are available in Western populations. The aim of this prospective study was to evaluate the relationship between viral Epstein-Barr DNA copy numbers in plasma and the response rate, progression-free survival and overall survival in a cohort of Western patients with stage IIb-IVb nasopharyngeal cancer.</p> <p>Methods</p> <p>We evaluated plasma samples from 36 consecutive patients treated with induction chemotherapy followed by chemoradiation. EBV copy numbers were determined after DNA extraction using real-time quantitative polymerase chain reaction. Survival curves were estimated using the Kaplan–Meier method.</p> <p>Results</p> <p>Circulating Epstein-Barr virus DNA levels were measured before treatment, at the end of concomitant chemo- and radiotherapy, and during the follow-up period. Pre-treatment levels significantly correlated with the initial stage and probability of relapse. Their increase was 100% specific and 71.3% sensitive in detecting loco-regional or metastatic recurrence (an overall accuracy of 94.4%). Three-year progression-free and overall survival were respectively 78.2% and 97.1%.</p> <p>Conclusions</p> <p>The results of this study confirm that patients from a Western country affected by loco-regionally advanced nasopharyngeal carcinoma have high plasma Epstein-Barr virus DNA levels at diagnosis. The monitoring of plasma levels is sensitive and highly specific in detecting disease recurrence and metastases.</p

Erratum to \u201cSystematic versus on-demand early palliative care: A randomised clinical trial assessing quality of care and treatment aggressiveness near the end of life\u201d [Eur J Cancer (2016) 69 (110\u2013118)] (S095980491632487X)(10.1016/j.ejca.2016.10.004)

The publisher regrets that the collaborators for this paper were not listed as such within the author details of the published paper. The collaborators were published in the Acknowledgements and are as follows: Alberto Farolfi, Silvia Ruscelli, Martina Valgiusti, Sara Pini, Marina Faedi, Department of Medical Oncology, IRST IRCCS, Meldola; Angela Ragazzini, Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola; Cristina Pittureri and Elena Amaducci, Palliative Care and Hospice Unit, AUSL Romagna, Cesena; Irene Guglieri, Psychooncology Service, Veneto Institute of Oncology IOV \u2013 IRCCS, Padua; Francesca Bergamo, Sara Lonardi, Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology IOV \u2013 IRCCS, Padua; Camilla Di Nunzio, Medical Oncology Unit, Oncology\u2013Hematology Department, Guglielmo da Saliceto Hospital, Piacenza; Monica Bosco, Palliative Care Unit, Oncology\u2013Hematology Department, Guglielmo da Saliceto Hospital, Piacenza; Barbara Bocci, Medical Oncology Unit, San Paolo Hospital, Milan; Alfina Bramanti and Chiara Gandini, Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia; Angela Buonadonna, Medical Oncology Unit, Aviano National Cancer Institute, Aviano; Alessandro Comandone, Medical Oncology Unit, Presidio Humanitas Gradenigo, Turin; Sonia Zoccali, Coordinamento Cure Palliative (supported by F.I.L.E., Leniterapia Italian Foundatio), Florence; Maria Simona Pino, Medical Oncology Unit, Oncology Department, S. Maria Annunziata Hospital, Florence; Davide Dalu, Palliative Care Unit, Oncology Department, L. Sacco Hospital, Milan; Pietro Sozzi, Oncology Unit, Ospedale degli Infermi, Ponderano; Alberto Gozza, Medical Oncology, Department of Medicine, E.O. Galliera Hospitals, Genoa; Monica Giordano and Carla Longhi, Oncology Unit, Sant'Anna Hospital, Como; Cristina Autelitano, Palliative Care Unit, Arcispedale S. Maria Nuova \u2013 IRCCS, Reggio Emilia; Teresa Gamucci, Oncology Unit, SS Trinit\ue0 Hospital Sora, ASL Frosinone, Frosinone; Cataldo Mastromauro, Oncology Unit, ULSS 12 Veneziana, Venice; Rodolfo Scognamiglio, Hospice Nazareth, Mestre; Daniela Degiovanni, Palliative Care Unit, Casale Monferrato, ASL Alessandria; Federica Negri, Medical Oncology Unit, Istituti Ospitalieri, Cremona; Augusto Caraceni, Palliative Care, Pain Therapy and Rehabilitation Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan; and Luigi Montanari, Palliative Care Unit Ravenna, AUSL Romagna, Italy. The publisher would like to apologise for any inconvenience caused