Thermodynamic energetics underlying genomic instability and whole-genome doubling in cancer

[en] Genomic instability is characteristic of the majority of cancers. It includes changes of copy numbers of genes and chromosomes during diverse cell processes, such as genome replication. Genomic instability is a strong biomarker of poor prognosis. An analysis of DNA copy numbers in human tumors across different cancers reveals an instability in an energetic sense: The free energy of the distribution of gene loci copy numbers in each tumor is found to be a monotonically increasing and universal function of the mean chromosome ploidy in that tumor. This relates the biological (genomic instability) with the physicochemical stability criterion. The analysis also shows that it is energetically more favorable for genome doubling to occur from a not-already-fragmented genome.Genomic instability contributes to tumorigenesis through the amplification and deletion of cancer driver genes. DNA copy number (CN) profiling of ensembles of tumors allows a thermodynamic analysis of the profile for each tumor. The free energy of the distribution of CNs is found to be a monotonically increasing function of the average chromosomal ploidy. The dependence is universal across several cancer types. Surprisal analysis distinguishes two main known subgroups: tumors with cells that have or have not undergone whole-genome duplication (WGD). The analysis uncovers that CN states having a narrower distribution are energetically more favorable toward the WGD transition. Surprisal analysis also determines the deviations from a fully stable-state distribution. These deviations reflect constraints imposed by tumor fitness selection pressures. The results point to CN changes that are more common in high-ploidy tumors and thus support altered selection pressures upon WGD.

Research center :

MolSys - Molecular Systems - ULiège

Disciplines :

Physical, chemical, mathematical & earth Sciences: Multidisciplinary, general & others

Author, co-author :

Remacle, Françoise ; Université de Liège - ULiège > Département de chimie (sciences) > Laboratoire de chimie physique théorique

Graeber, Thomas G.

Levine, R. D.

Language :

English

Title :

Thermodynamic energetics underlying genomic instability and whole-genome doubling in cancer

Publication date :

2020

Journal title :

Proceedings of the National Academy of Sciences of the United States of America

ISSN :

0027-8424

eISSN :

1091-6490

Volume :

117

Issue :

Pages :

18880

Peer reviewed :

Peer reviewed

Additional URL :

http://www.pnas.org/content/117/31/18880.abstract

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]

Available on ORBi :

since 26 January 2021

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