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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.<\/jats:p>","DOI":"10.3390\/cancers11030391","type":"journal-article","created":{"date-parts":[[2019,3,21]],"date-time":"2019-03-21T04:11:56Z","timestamp":1553141516000},"page":"391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A Systematic Pan-Cancer Analysis of Genetic Heterogeneity Reveals Associations with Epigenetic Modifiers"],"prefix":"10.3390","volume":"11","author":[{"given":"Mafalda Ramos","family":"de Matos","sequence":"first","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]},{"given":"Ioana","family":"Posa","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0074-0741","authenticated-orcid":false,"given":"Filipa Sofia","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]},{"given":"Vanessa Alexandra","family":"Morais","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6974-4209","authenticated-orcid":false,"given":"Ana Rita","family":"Grosso","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"},{"name":"UCIBIO, Departamento de Ci\u00eancias da Vida, Faculdade de Ci\u00eancias e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal"}]},{"given":"S\u00e9rgio Fernandes","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Burrell, R.A., McGranahan, N., Bartek, J., and Swanton, C. 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