Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas
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- 作者：Adam M. Fontebasso (1)
Jeremy Schwartzentruber (2)
Dong-Anh Khuong-Quang (3)
Xiao-Yang Liu (3)
Dominik Sturm (4)
Andrey Korshunov (5)
David T. W. Jones (4)
Hendrik Witt (4) (6)
Marcel Kool (4)
Steffen Albrecht (7)
Adam Fleming (8)
Djihad Hadjadj (3)
Stephan Busche (3)
Pierre Lepage (2)
Alexandre Montpetit (2)
Alfredo Staffa (2)
Noha Gerges (3)
Magdalena Zakrzewska (9)
Krzystof Zakrzewski (10)
Pawel P. Liberski (9)
Peter Hauser (11)
Miklos Garami (11)
Almos Klekner (12)
Laszlo Bognar (12)
Gelareh Zadeh (13)
Damien Faury (3)
Stefan M. Pfister (4) (6)
Nada Jabado (1) (14) (3) (8)
Jacek Majewski (2) (3) - 关键词：High ; grade glioma ; H3K36 methylation ; SETD2 ; Epigenetic ; Pediatric ; Young adult
- 刊名：Acta Neuropathologica
- 出版年：2013
- 出版时间：May 2013
- 年：2013
- 卷：125
- 期：5
- 页码：659-669
- 全文大小：714KB
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Jeremy Schwartzentruber (2)
Dong-Anh Khuong-Quang (3)
Xiao-Yang Liu (3)
Dominik Sturm (4)
Andrey Korshunov (5)
David T. W. Jones (4)
Hendrik Witt (4) (6)
Marcel Kool (4)
Steffen Albrecht (7)
Adam Fleming (8)
Djihad Hadjadj (3)
Stephan Busche (3)
Pierre Lepage (2)
Alexandre Montpetit (2)
Alfredo Staffa (2)
Noha Gerges (3)
Magdalena Zakrzewska (9)
Krzystof Zakrzewski (10)
Pawel P. Liberski (9)
Peter Hauser (11)
Miklos Garami (11)
Almos Klekner (12)
Laszlo Bognar (12)
Gelareh Zadeh (13)
Damien Faury (3)
Stefan M. Pfister (4) (6)
Nada Jabado (1) (14) (3) (8)
Jacek Majewski (2) (3)
1. Division of Experimental Medicine, McGill University and McGill University Health Centre, Montreal, QC, Canada
2. McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada
3. Department of Human Genetics, McGill University and McGill University Health Centre, Montreal, QC, Canada
4. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
5. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
6. Department of Paediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
7. Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada
8. Division of Hemato-Oncology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada
9. Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland
10. Department of Neurosurgery, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
11. 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
12. Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
13. Division of Neurosurgery, Toronto Western Hospital, Ontario, Canada
14. Department of Paediatrics, The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada - ISSN：1432-0533
文摘
Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30?% of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15?% of pediatric HGGs, a result that was genome-wide significant (FDR?=?0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15?% of pediatric HGGs (11/73) and 8?% of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P?=?0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P?=?0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P?<?0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.