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Open AccessArticle

A Systematic Pan-Cancer Analysis of Genetic Heterogeneity Reveals Associations with Epigenetic Modifiers

1
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal
2
UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(3), 391; https://doi.org/10.3390/cancers11030391
Received: 12 February 2019 / Revised: 9 March 2019 / Accepted: 17 March 2019 / Published: 20 March 2019
(This article belongs to the Special Issue Application of Bioinformatics in Cancers)
Intratumor genetic heterogeneity (ITH) is the main obstacle to effective cancer treatment and a major mechanism of drug resistance. It results from the continuous evolution of different clones of a tumor over time. However, the molecular features underlying the emergence of genetically-distinct subclonal cell populations remain elusive. Here, we conducted an exhaustive characterization of ITH across 2807 tumor samples from 16 cancer types. Integration of ITH scores and somatic variants detected in each tumor sample revealed that mutations in epigenetic modifier genes are associated with higher ITH levels. In particular, genes that regulate genome-wide histone and DNA methylation emerged as being determinant of high ITH. Indeed, the knockout of histone methyltransferase SETD2 or DNA methyltransferase DNMT3A using the CRISPR/Cas9 system on cancer cells led to significant expansion of genetically-distinct clones and culminated in highly heterogeneous cell populations. The ITH scores observed in knockout cells recapitulated the heterogeneity levels observed in patient tumor samples and correlated with a better mitochondrial bioenergetic performance under stress conditions. Our work provides new insights into tumor development, and discloses new drivers of ITH, which may be useful as either predictive biomarkers or therapeutic targets to improve cancer treatment. View Full-Text
Keywords: cancer; intratumor heterogeneity; genomic instability; epigenetics; mitochondrial metabolism cancer; intratumor heterogeneity; genomic instability; epigenetics; mitochondrial metabolism
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MDPI and ACS Style

de Matos, M.R.; Posa, I.; Carvalho, F.S.; Morais, V.A.; Grosso, A.R.; de Almeida, S.F. A Systematic Pan-Cancer Analysis of Genetic Heterogeneity Reveals Associations with Epigenetic Modifiers. Cancers 2019, 11, 391. https://doi.org/10.3390/cancers11030391

AMA Style

de Matos MR, Posa I, Carvalho FS, Morais VA, Grosso AR, de Almeida SF. A Systematic Pan-Cancer Analysis of Genetic Heterogeneity Reveals Associations with Epigenetic Modifiers. Cancers. 2019; 11(3):391. https://doi.org/10.3390/cancers11030391

Chicago/Turabian Style

de Matos, Mafalda R.; Posa, Ioana; Carvalho, Filipa S.; Morais, Vanessa A.; Grosso, Ana R.; de Almeida, Sérgio F. 2019. "A Systematic Pan-Cancer Analysis of Genetic Heterogeneity Reveals Associations with Epigenetic Modifiers" Cancers 11, no. 3: 391. https://doi.org/10.3390/cancers11030391

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