Jonathan So1, Yasin Mamatjan2, Gelareh Zadeh2,3, Kenneth Aldape4, Fabio Y Moraes5. 1. Radiation Medicine Program, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada. 2. Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Centre, University of Toronto and MacFeeters-Hamilton Centre for Neuro-Oncology Research, Toronto, Ontario, Canada. 3. Department of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. 4. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. 5. Department of Radiation Oncology, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada.
Abstract
BACKGROUND: Recent international sequencing efforts have allowed for the molecular taxonomy of lower-grade gliomas (LGG). We sought to analyze The Cancer Genome Atlas (TCGA, 2015) gene expression datasets on molecularly defined oligodendrogliomas (IDH-mutated and 1p/19q-codeleted) patients treated with adjuvant radiation or those observed to discover prognostic markers and pathways. METHODS: mRNA expression and clinical information of patients with oligodendroglioma were taken from the TCGA "Brain Lower Grade Glioma" provisional dataset. Transcription factor network reconstruction and analysis were performed using the R packages "RTN" and "RTNsurvival." Elastic net regularization and survival modeling were performed using the "biospear," "plsRCox," "survival" packages. RESULTS: From our cohort of 137 patients, 65 received adjuvant radiation and 72 were observed. In the cohort that received adjuvant radiotherapy, a transcription factor activity signature, that correlated with hypoxia, was associated with shorter disease-free survival (DFS) (median = 45 months vs 108 months, P < .001). This increased risk was not seen in patients who were observed (P = .2). Within the observation cohort, a transcription factor activity signature was generated that was associated with poor DFS (median = 72 months. vs 143 months., P < .01). CONCLUSIONS: We identified a transcription factor activity signature associated with poor prognosis in patients with molecular oligodendroglioma treated with adjuvant radiotherapy. These patients would be potential candidates for treatment intensification. A second signature was generated for patients who were more likely to progress on observation. This potentially identifies a cohort who would benefit from upfront adjuvant radiotherapy.
BACKGROUND: Recent international sequencing efforts have allowed for the molecular taxonomy of lower-grade gliomas (LGG). We sought to analyze The Cancer Genome Atlas (TCGA, 2015) gene expression datasets on molecularly defined oligodendrogliomas (IDH-mutated and 1p/19q-codeleted) patients treated with adjuvant radiation or those observed to discover prognostic markers and pathways. METHODS: mRNA expression and clinical information of patients with oligodendroglioma were taken from the TCGA "Brain Lower Grade Glioma" provisional dataset. Transcription factor network reconstruction and analysis were performed using the R packages "RTN" and "RTNsurvival." Elastic net regularization and survival modeling were performed using the "biospear," "plsRCox," "survival" packages. RESULTS: From our cohort of 137 patients, 65 received adjuvant radiation and 72 were observed. In the cohort that received adjuvant radiotherapy, a transcription factor activity signature, that correlated with hypoxia, was associated with shorter disease-free survival (DFS) (median = 45 months vs 108 months, P < .001). This increased risk was not seen in patients who were observed (P = .2). Within the observation cohort, a transcription factor activity signature was generated that was associated with poor DFS (median = 72 months. vs 143 months., P < .01). CONCLUSIONS: We identified a transcription factor activity signature associated with poor prognosis in patients with molecular oligodendroglioma treated with adjuvant radiotherapy. These patients would be potential candidates for treatment intensification. A second signature was generated for patients who were more likely to progress on observation. This potentially identifies a cohort who would benefit from upfront adjuvant radiotherapy.
Authors: Louis Burt Nabors; Jana Portnow; Mario Ammirati; Joachim Baehring; Henry Brem; Nicholas Butowski; Robert A Fenstermaker; Peter Forsyth; Jona Hattangadi-Gluth; Matthias Holdhoff; Steven Howard; Larry Junck; Thomas Kaley; Priya Kumthekar; Jay S Loeffler; Paul L Moots; Maciej M Mrugala; Seema Nagpal; Manjari Pandey; Ian Parney; Katherine Peters; Vinay K Puduvalli; John Ragsdale; Jason Rockhill; Lisa Rogers; Chad Rusthoven; Nicole Shonka; Dennis C Shrieve; Allen K Sills; Lode J Swinnen; Christina Tsien; Stephanie Weiss; Patrick Yung Wen; Nicole Willmarth; Mary Anne Bergman; Anita Engh Journal: J Natl Compr Canc Netw Date: 2017-11 Impact factor: 11.908
Authors: Melike Pekmezci; Terri Rice; Annette M Molinaro; Kyle M Walsh; Paul A Decker; Helen Hansen; Hugues Sicotte; Thomas M Kollmeyer; Lucie S McCoy; Gobinda Sarkar; Arie Perry; Caterina Giannini; Tarik Tihan; Mitchel S Berger; Joseph L Wiemels; Paige M Bracci; Jeanette E Eckel-Passow; Daniel H Lachance; Jennifer Clarke; Jennie W Taylor; Tracy Luks; John K Wiencke; Robert B Jenkins; Margaret R Wrensch Journal: Acta Neuropathol Date: 2017-03-02 Impact factor: 15.887
Authors: Michael N C Fletcher; Mauro A A Castro; Xin Wang; Ines de Santiago; Martin O'Reilly; Suet-Feung Chin; Oscar M Rueda; Carlos Caldas; Bruce A J Ponder; Florian Markowetz; Kerstin B Meyer Journal: Nat Commun Date: 2013 Impact factor: 14.919