Aneuploidy and chromosomal instability in cancer: a jackpot to chaos

Giam, Maybelline; Rancati, Giulia

doi:10.1186/s13008-015-0009-7

Cited by 214 publications

(178 citation statements)

References 134 publications

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“…Paradoxically, high incidence of CIN may be responsible for a relatively indolent clinical course in most cases, since excessive CIN frequently hampers tumor progression [58]. Aneuploidic cells can be selectively targeted by energy and proteotoxic stress-inducing compounds (e.g.…”

Section: Cytogenetic Alterationsmentioning

confidence: 99%

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

2016

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Olfactory neuroblastoma (ONB, Esthesioneuroblastoma) is an infrequent neoplasm of the head and neck area derived from olfactory neuroepithelium. Despite relatively good prognosis a subset of patients shows recurrence, progression and/or metastatic disease, which requires additional treatment. However, neither prognostic nor predictive factors are well specified. Thus, we performed a literature search for the currently available data on disturbances in molecular pathways, cytogenetic changes and results gained by next generation sequencing (NGS) approaches in ONB in order to gain an overview of genetic alterations which might be useful for treating patients with ONB. We present briefly ONB molecular pathogenesis and propose potential therapeutic targets and prognostic factors. Possible therapeutic targets in ONB include: receptor tyrosine kinases (c-kit, PDGFR-b, TrkB; EGFR); somatostatin receptor; FGF-FGFR1 signaling; Sonic hedgehog pathway; apoptosis-related pathways (Bcl-2, TRAIL) and neoangiogenesis (VEGF; KDR). Furthermore, we compare high- and low-grade ONB, and describe its frequent mimicker: sinonasal neuroendocrine carcinoma. ONB is often a therapeutic challenge, so our goal should be the implementation of acquired knowledge into clinical practice, especially at pretreated, recurrent and metastatic stages. Moreover, the multicenter molecular studies are needed to increase the amount of available data.

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Section: Cytogenetic Alterationsmentioning

confidence: 99%

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

2016

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“…TAF12 (or transcription initiation factor IID subunit 12) is a component of the TFIID general transcription factor that is involved in RNA polymerase II-dependent transcription (87). Transcription is a process that has many links to genome instability, and aneuploidy-induced transcriptional changes are just one possible method used by cancer cells to escape cellular homeostasis mechanisms (88). Recent work identified TAF12 as an oncogene involved in the formation of choroid plexus carcinomas, a frequently lethal brain tumor (55).…”

Section: Rms Lines Expressingmentioning

confidence: 99%

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Duffy

Fam

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.dosage chromosome instability | overexpression | synthetic dosage lethality | TDP1 | rhabdomyosarcoma

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“…However, clearly, the consequences of CIN are different in vivo and in vitro; and therefore, we cannot assume in vitro data to be representative of how human cells respond to CIN in vivo. Creating better models to observe the physiological consequences of CIN in vivo is thus vitally important, especially since genomic instability is a hallmark of both cancer and aging, [78,79] 7. What Effect Do CIN and Aneuploidy Have on Cancer?…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 99%

CIN and Aneuploidy: Different Concepts, Different Consequences

Schukken

Foijer

2017

BioEssays

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Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg

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Aneuploidy and chromosomal instability in cancer: a jackpot to chaos

Cited by 214 publications

References 134 publications

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

CIN and Aneuploidy: Different Concepts, Different Consequences

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