Chromatin organization is a major influence on regional mutation rates in human cancer cells

Schuster-Böckler, Benjamin; Lehner, Ben

doi:10.1038/nature11273

Cited by 622 publications

(628 citation statements)

References 29 publications

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“…The mutation spectrum thus resembles that of mutations that occurred in germ cells and persisted in the offspring population, often with no pathogenic effects (dbSNP) but distinctly different from that of diseaseassociated mutations (ClinVar). These results are in agreement with recent findings that chromatin organization influences the genomic susceptibility to acquire somatic mutations (Michaelson et al 2012;Schuster-Bockler and Lehner 2012).…”

Section: Somatic Mutations Routinely Occur In the Blood Genomesupporting

confidence: 83%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

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The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

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Section: Somatic Mutations Routinely Occur In the Blood Genomesupporting

confidence: 83%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

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“…In addition, this study also showed that BLIMP1/ PRMT5 and histone H2A and H4 arginine 3 dimethylation are present in CIS and most seminomas, and less in EC and other nonseminomas. Recently, Schuster-Böckler and Lehner showed that chromatin organization has a major influence on regional mutation rates (Schuster-Bockler and Lehner, 2012). Mutation rates were positively correlated with heterochromatin related marks, of which histone modification H3K9Me3 was most important, and accounted for more than 40% of the somatic mutation variants (Schuster-Bockler and Lehner, 2012).…”

Section: Germ Cell Development and Gccmentioning

confidence: 99%

“…Recently, Schuster-Böckler and Lehner showed that chromatin organization has a major influence on regional mutation rates (Schuster-Bockler and Lehner, 2012). Mutation rates were positively correlated with heterochromatin related marks, of which histone modification H3K9Me3 was most important, and accounted for more than 40% of the somatic mutation variants (Schuster-Bockler and Lehner, 2012). The open chromatin in regions involved in embryonic development showed a negative association, which is in line with the fact that mutations are rarely found in GCC and the idea that the germ line is protected for mutations (immortal strand).…”

Section: Germ Cell Development and Gccmentioning

confidence: 99%

Role of epigenetics in the etiology of germ cell cancer

Zwan¹,

Stoop²,

Rossello³

et al. 2013

Int. J. Dev. Biol.

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Embryonic development is strictly controlled by functionality of genes in which the existing networks can act both on transcription and translation regulation. Germ cell cancers (GCC) are unique because of a number of characteristics. In spite of their clinical presentation, i.e., predominantly after puberty, they arise from primordial germ cells/gonocytes that have failed appropriate maturation to either pre-spermatogonia or oogonia. GCC mimic embryonal development to a certain extent, including capacity for totipotency. This knowledge has allowed the identification of informative diagnostic markers, including OCT3/4 (POU5F1), SOX2 and SOX17. An additional marker is the overall demethylated status of the genome. Genetic mutations in GCC are rare, which is exceptional for solid cancers. Our hypothesis is that a disturbed epigenetic regulation (through combined interaction of genetic or environmental parameters; referred to as genvironment) affect embryonic germ cell development, resulting in delayed or blocked maturation, and potentially progression to GCC. In this respect, studies of patients with Disorders of Sex Development (DSD) have increased our knowledge significantly. Genvironmental influences can lead to retention of existence of embryonic germ cells, the first step in the pathogenesis of GCC, resulting into the precursor lesions gonadoblastoma or carcinoma in situ. Identification of epigenetic alterations could lead to better understanding these processes and development of specific markers for early detection, eventually leading to development of targeted treatment. This review describes an interactive model related to the role of epigenetics in GCC pathogenesis, focusing on DNA methylation, histone modifications, epigenetic memory and inheritance, as well as environmental factors.

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“…14,16 Transcription of satellite DNA is naturally repressed by the compact structure of heterochromatin; thus, its overexpression has been associated with genomic instability. 17,18 The implications of heterochromatin structure in human cancer have been recently highlighted by the dramatic correlation between the mutation rates of the cancer genome and heterochromatin, 19 and by the overexpression of heterochromatic satellite DNA sequence in diverse mouse and human cancers. 20 In the present study, we identify a link between PTEN and heterochromatin.…”

Section: Introductionmentioning

confidence: 99%

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

et al. 2015

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The tumor suppressor, PTEN, is one of the most commonly mutated genes in cancer. Recently, PTEN has been shown to localize in the nucleus and is required to maintain genomic stability. Here, we show that nuclear PTEN, independent of its phosphatase activity, is essential for maintaining heterochromatin structure. Depletion of PTEN leads to loss of heterochromatic foci, decreased chromatin compaction, overexpression of heterochromatic genes, and reduced protein stability of heterochromatin protein 1 a. We found that the C-terminus of PTEN is required to maintain heterochromatin structure. Additionally, cancer-associated PTEN mutants lost their tumor-suppressor function when their heterochromatin structure was compromised. We propose that this novel role of PTEN accounts for its function in guarding genomic stability and suppressing tumor development.

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Chromatin organization is a major influence on regional mutation rates in human cancer cells

Cited by 622 publications

References 29 publications

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

Role of epigenetics in the etiology of germ cell cancer

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

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