Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 50...

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Detalles Bibliográficos
Autores: TRACERx Renal Consortium, López Fernández de Villaverde, José Ignacio
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/30696
Acceso en línea:http://hdl.handle.net/10810/30696
Access Level:acceso abierto
Palabra clave:tert promoter mutations
copy-number
somatic mutations
kidney cancer
hTERT gene
C-Myc
carcinoma
chromothripsis
transcription
patterns
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spelling Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx RenalTRACERx Renal ConsortiumLópez Fernández de Villaverde, José Ignaciotert promoter mutationscopy-numbersomatic mutationskidney cancerhTERT geneC-MyccarcinomachromothripsistranscriptionpatternsClear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 50 UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.We thank Eleanor Carlyle, Aida Murra, Justine Korteweg, Kim Edmonds, Karla Lingard, Karen O'Meara, Helen Breeze, Lesley Cooper, Linda Shephard, Sharanpreet Lall, Sarah Sarker, and Leonora Conneely for study support. We thank members of the HeritX organization for discussions on prevention of inherited cancers. We thank the patients and their families. The work presented in this manuscript was funded by EU FP7 (project PREDICT ID number 259303) and the Wellcome Trust and Cancer Research UK. S. T. is funded by Cancer Research UK (C50947/A18176). S. T., J. L., and M. G. receive funding from the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (A109). J. H. R. F. and A. G. L. were supported by the University of Cambridge, Cancer Research UK (C14303/A17197), and Hutchison Whampoa. K. L. is supported by a UK Medical Research Council Skills Development Fellowship Award. C. S. is funded by Cancer Research UK (TRACERx), the Rosetrees Trust, NovoNordisk Foundation (16584), EU FP7 (projects PREDICT and RESPONSIFY, ID number 259303), the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council (THESEUS), and National Institute for Health Research University College London Hospitals Biomedical Research Centre. P. J. C. has a Wellcome Trust Senior Clinical Research Fellowship (WT088340MA).Cell Press201920192018info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/30696reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttps://www.sciencedirect.com/science/article/pii/S0092867418301648?via%3Dihubinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Atribución 3.0 Españaoai:addi.ehu.eus:10810/306962026-06-18T09:23:17Z
dc.title.none.fl_str_mv Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
title Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
spellingShingle Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
TRACERx Renal Consortium
tert promoter mutations
copy-number
somatic mutations
kidney cancer
hTERT gene
C-Myc
carcinoma
chromothripsis
transcription
patterns
title_short Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
title_full Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
title_fullStr Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
title_full_unstemmed Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
title_sort Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
dc.creator.none.fl_str_mv TRACERx Renal Consortium
López Fernández de Villaverde, José Ignacio
author TRACERx Renal Consortium
author_facet TRACERx Renal Consortium
López Fernández de Villaverde, José Ignacio
author_role author
author2 López Fernández de Villaverde, José Ignacio
author2_role author
dc.subject.none.fl_str_mv tert promoter mutations
copy-number
somatic mutations
kidney cancer
hTERT gene
C-Myc
carcinoma
chromothripsis
transcription
patterns
topic tert promoter mutations
copy-number
somatic mutations
kidney cancer
hTERT gene
C-Myc
carcinoma
chromothripsis
transcription
patterns
description Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 50 UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/30696
url http://hdl.handle.net/10810/30696
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://www.sciencedirect.com/science/article/pii/S0092867418301648?via%3Dihub
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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