Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas.

Adenocarcinoma / genetics Esophageal Neoplasms / genetics Genome, Human Histone Acetyltransferases / genetics Humans Whole Genome Sequencing

Journal

Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179

Informations de publication

Date de publication:
08 04 2022
Historique:
received: 07 09 2021
accepted: 25 02 2022
entrez: 9 4 2022
pubmed: 10 4 2022
medline: 13 4 2022
Statut: epublish

Résumé

Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.

Identifiants

DOI: 10.1038/s42003-022-03238-7 PMID: 35396535 PMC: PMC8993906
pubmed: 35396535
doi: 10.1038/s42003-022-03238-7
pii: 10.1038/s42003-022-03238-7
pmc: PMC8993906
doi:

Substances chimiques

Histone Acetyltransferases EC 2.3.1.48
KAT6B protein, human EC 2.3.1.48

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

335

Subventions

Organisme : Cancer Research UK
ID : 15874
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/W014122/1
Pays : United Kingdom
Organisme : Department of Health
ID : BRC-1215-20014
Pays : United Kingdom
Organisme : Medical Research Council
ID : RG84369
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 23924
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 20406
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 25487
Pays : United Kingdom

Investigateurs

Nicola Grehan (N)
Barbara Nutzinger (B)
Elwira Fidziukiewicz (E)
Adam Freeman (A)
Elizabeth C Smyth (EC)
Maria O'Donovan (M)
Ahmad Miremadi (A)
Shalini Malhotra (S)
Monika Tripathi (M)
Calvin Cheah (C)
Hannah Coles (H)
Connor Flint (C)
Matthew Eldridge (M)
Maria Secrier (M)
Sriganesh Jammula (S)
Jim Davies (J)
Charles Crichton (C)
Nick Carroll (N)
Richard H Hardwick (RH)
Peter Safranek (P)
Andrew Hindmarsh (A)
Vijayendran Sujendran (V)
Stephen J Hayes (SJ)
Yeng Ang (Y)
Andrew Sharrocks (A)
Shaun R Preston (SR)
Izhar Bagwan (I)
Vicki Save (V)
Richard J E Skipworth (RJE)
Ted R Hupp (TR)
J Robert O'Neill (JR)
Olga Tucker (O)
Andrew Beggs (A)
Philippe Taniere (P)
Sonia Puig (S)
Timothy J Underwood (TJ)
Robert C Walker (RC)
Ben L Grace (BL)
Jesper Lagergren (J)
James Gossage (J)
Andrew Davies (A)
Fuju Chang (F)
Ula Mahadeva (U)
Vicky Goh (V)
Francesca D Ciccarelli (FD)
Grant Sanders (G)
Richard Berrisford (R)
David Chan (D)
Ed Cheong (E)
Bhaskar Kumar (B)
L Sreedharan (L)
Simon L Parsons (SL)
Irshad Soomro (I)
Philip Kaye (P)
John Saunders (J)
Laurence Lovat (L)
Rehan Haidry (R)
Michael Scott (M)
Sharmila Sothi (S)
Suzy Lishman (S)
George B Hanna (GB)
Christopher J Peters (CJ)
Krishna Moorthy (K)
Anna Grabowska (A)
Richard Turkington (R)
Damian McManus (D)
Helen Coleman (H)
Russell D Petty (RD)
Freddie Bartlett (F)

Informations de copyright

© 2022. The Author(s).

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Auteurs

Alvin Wei Tian Ng (AWT)

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
ORCID: 0000-0003-4672-0815

Gianmarco Contino (G)

Institute of Cancer and Genomic Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, UK.
University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2GW, UK.

Sarah Killcoyne (S)

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
European Molecular Biology Laboratory, European Bioinformatics Institute EMBL-EBI, Hinxton, UK.

Ginny Devonshire (G)

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
ORCID: 0000-0002-1408-8176

Ray Hsu (R)

Department of Surgery, University of Cambridge, Cambridge, UK.

Sujath Abbas (S)

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

Jing Su (J)

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

Aisling M Redmond (AM)

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

Jamie M J Weaver (JMJ)

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
Department of Pathology, University of Cambridge, Cambridge, UK.

Matthew D Eldridge (MD)

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
ORCID: 0000-0002-5799-8911

Simon Tavaré (S)

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Irving Institute for Cancer Dynamics, Columbia University, New York, USA.
Department of Statistics, Columbia University, New York, USA.
Department of Biological Sciences, Columbia University, New York, USA.

Paul A W Edwards (PAW)

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Department of Pathology, University of Cambridge, Cambridge, UK.
ORCID: 0000-0002-4789-3374

Rebecca C Fitzgerald (RC)

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK. rcf29@cam.ac.uk.
ORCID: 0000-0002-3434-3568

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Classifications MeSH

questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Rearrangement processes and structural...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Tumeurs gastro-intestinales › Tumeurs de l'oesophage › Rearrangement processes and structural...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Génome humain › Rearrangement processes and structural...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Acyltransferases › Acetyltransferases › Lysine acetyltransferases › Histone acetyltransferases › Rearrangement processes and structural...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Rearrangement processes and structural...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Rearrangement processes and structural...