Processed pseudogenes acquired somatically during cancer development.
Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Susanna L
SL
Cooke
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Adam
A
Shlien
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
John
J
Marshall
Lungs for Living Research Centre, Rayne Institute, University College London, London WC1E 6JF, UK.
Christodoulos P
CP
Pipinikas
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Inigo
I
Martincorena
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Jose M C
JM
Tubio
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Yilong
Y
Li
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Andrew
A
Menzies
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Laura
L
Mudie
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Manasa
M
Ramakrishna
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Lucy
L
Yates
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Helen
H
Davies
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [2] University of Cambridge, Cambridge CB2 0XY, UK.
Niccolo
N
Bolli
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Graham R
GR
Bignell
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Patrick S
PS
Tarpey
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [2] University of Cambridge, Cambridge CB2 0XY, UK.
Sam
S
Behjati
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Serena
S
Nik-Zainal
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Elli
E
Papaemmanuil
Lungs for Living Research Centre, Rayne Institute, University College London, London WC1E 6JF, UK.
Vitor H
VH
Teixeira
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Keiran
K
Raine
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Sarah
S
O'Meara
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Maryam S
MS
Dodoran
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Jon W
JW
Teague
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Adam P
AP
Butler
Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Christine
C
Iacobuzio-Donahue
Addenbrooke's NHS Foundation Trust, Cambridge CB2 0QQ, UK.
Thomas
T
Santarius
Children's Brain Tumour Research Centre, University of Nottingham, Nottingham NG7 2UH, UK.
Richard G
RG
Grundy
Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8.
David
D
Malkin
Institute for Cancer Research, Sutton, London SM2 5NG, UK.
Mel
M
Greaves
Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Nikhil
N
Munshi
1] Lungs for Living Research Centre, Rayne Institute, University College London, London WC1E 6JF, UK [2] Royal National Orthopaedic Hospital, Middlesex HA7 4LP, UK.
Adrienne M
AM
Flanagan
Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
David
D
Bowtell
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Sancha
S
Martin
Denis
D
Larsimont
Department of Pathology, Memorial-Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Jorge S
JS
Reis-Filho
1] Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia [2] Department of Gastroenterology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3050, Australia.
Alex
A
Boussioutas
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27713, USA.
Jack A
JA
Taylor
UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Neil D
ND
Hayes
Lungs for Living Research Centre, Rayne Institute, University College London, London WC1E 6JF, UK.
Sam M
SM
Janes
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
P Andrew
PA
Futreal
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Michael R
MR
Stratton
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [2] Addenbrooke's NHS Foundation Trust, Cambridge CB2 0QQ, UK.
Ultan
U
McDermott
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [2] University of Cambridge, Cambridge CB2 0XY, UK [3] Addenbrooke's NHS Foundation Trust, Cambridge CB2 0QQ, UK.
Peter J
PJ
Campbell
D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011544:Pseudogenes / Q000235:genetics* / Q000502:physiology