Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/13729
Título
Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers.
Autor(es)
Fecha de publicación
2021-12-03
Cita
Nat Commun . 2021;12(1):7051.
Idioma
Inglés
Tipo de documento
journal article
Resumen
The classic two-hit model posits that both alleles of a tumor suppressor gene (TSG) must be inactivated to cause cancer. In contrast, for some oncogenes and haploinsufficient TSGs, a single genetic alteration can suffice to increase tumor fitness. Here, by quantifying the interactions between mutations and copy number alterations (CNAs) across 10,000 tumors, we show that many cancer genes actually switch between acting as one-hit or two-hit drivers. Third order genetic interactions identify the causes of some of these switches in dominance and dosage sensitivity as mutations in other genes in the same biological pathway. The correct genetic model for a gene thus depends on the other mutations in a genome, with a second hit in the same gene or an alteration in a different gene in the same pathway sometimes representing alternative evolutionary paths to cancer.
Palabras clave
MESH
Genes, Tumor Suppressor | Models, Genetic | Oncogenes | Alleles | Carcinogenesis | DNA Copy Number Variations | Datasets as Topic | Haploinsufficiency | Humans | Mutation | Neoplasms
Descripción
We thank Luis Garcia-Jimeno for assistance with permutation. S.P. is supported by the Agencia Estatal de Investigacion, Ministerio de Ciencia e Innovacion (MCIN/AEI/10.13039/501100011033) through the RETOS project PID2019-109571RA-I00. This work was funded by the European Research Council (ERC) Starting grant (HYPER-INSIGHT, 757700) to F.S. and ERC Consolidator (IR-DC, 616434) and Advanced (MUTANOMICS, 883742) grants to B.L. F.S. and B.L. are funded by the ICREA Research Professor program. S.P., F.S., and B.L. acknowledge the support of the Severo Ochoa Centres of Excellence program to the CNIO, IRB Barcelona, and to the CRG (MCIN/AEI/10.13039/50110001103), respectively. B.L. and F.S. Work is funded with the grants BFU2017-89488-P and RegioMut BFU2017-89833-P (MCIN/AEI/10.13039/501100011033/FEDER "A way to make Europe"), respectively. B.L. is further supported by the Bettencourt Schueller Foundation, the Agencia de Gestio d'Ajuts Universitaris i de Recerca (2017 SGR 1322), and the Centres de Recerca de Catalunya (CERCA) program/Generalitat de Catalunya. B.L. also acknowledges the support of the Spanish Ministry of Economy, Industry, and Competitiveness to the European Molecular Biology Laboratory (EMBL) partnership. The results shown here are in whole or part based upon data generated by the TCGA Research Network.
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