The second hit of DNA methylation

Ruscio, Annalisa Di; Welner, Robert S.; Tenen, Daniel G.; Amabile, Giovanni

doi:10.1080/23723556.2015.1093690

Cited by 8 publications

(7 citation statements)

References 9 publications

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“…It is important to clarify that the epigenome plays a role in the two-hit hypothesis either on its own (with evidence to support the role of DNA methylation as the second hit ( 101 )) or by exerting its effect on tumour suppressor genes through the process of epigenetic silencing ( 102 ). Our hypothesis presented in this manuscript thus represents a variation from the long-held dogmas of carcinogenesis, namely, the inherited genetic susceptibility and acquired two-hit hypothesis (of Knudson) ( 18 ).…”

Section: Increased Cancer Risk In the Offspringmentioning

confidence: 99%

Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome

Barreto

Pandol

2021

Front. Oncol.

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The last decade has witnessed a significant rise in cancers in young adults. This spectrum of solid organ cancers occurring in individuals under the age of 40 years (some reports extending the age-group to <50 years) in whom aetiology of cancer cannot be traced back to pre-existing familial cancer syndromes, is referred to as termed young-, or early- onset cancers. The underlying causes for young-onset carcinogenesis have remained speculative. We recently proposed a hypothesis to explain the causation of this entity. We propose that the risk for young-onset cancer begins in the perinatal period as a result of the exposure of the foetus to stressors, including maternal malnutrition, smoking or alcohol, with the consequent epigenomic events triggered to help the foetus cope/adapt. Exposure to the same stressors, early in the life of that individual, facilitates a re-activation of these ‘responses designed to be protective’ but ultimately resulting in a loss of regulation at a metabolic and/or genetic level culminating in the evolution of the neoplastic process. In this manuscript, we will provide a rationale for this hypothesis and present evidence to further support it by clarifying the pathways involved, including elucidating a role for Acetyl-CoA and its effect on the epigenome. We present strategies and experimental models that can be used to test the hypothesis. We believe that a concerted effort by experts in different, but complementary fields, such as epidemiology, genetics, and epigenetics united towards the common goal of deciphering the underlying cause for young-onset cancers is the urgent need. Such efforts might serve to prove, or disprove, the presented hypothesis. However, the more important aim is to develop strategies to reverse the disturbing trend of the rise in young-onset cancers.

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Section: Increased Cancer Risk In the Offspringmentioning

confidence: 99%

Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome

Barreto

Pandol

2021

Front. Oncol.

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“…This is also why genetic history of cancer makes it far more likely for it to occur down the line. This further exemplifies the consequential role DNA methylation plays in initiating cancer [33]. DNA methylation also often leads to and is indicative of the Warburg Effect, a hallmark of cancer in which cells consume significantly higher amounts of glucose and perform glycolysis at higher rates and preferentially produce lactose, even in the presence of adequate oxygen [34].…”

Section: The Epigenome and Its Elementsmentioning

confidence: 90%

Epigenetics and Cancer: A Comprehensive Review

Pathak

Tomar²,

Pathak

2023

Asian Pac J Cancer Biol

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Cancer is a disease with extraordinary clinical significance, with much of medical research being devoted to it. Innumerable factors are relevant in fully understanding cancer but the epigenetic aspect stands out. Epigenetics is the study of changes, often germ-line, to the genome affecting the gene expression by silencing certain genes and modifying the gene expression. The three primary mechanisms for epigenetic changes are DNA methylation, histone modification and non-coding RNA (ncRNA) associated gene silencing. While epigenetics is a pivotal mechanism for the regular maintenance of a myriad of processes- including in cell differentiation and adaptability- aberrant epigenetic changes can lead to depreciated/altered gene function which may ultimately culminate in cancer. Consequently, the connection between epigenetics and cancer has been intensely studied over the past two decades and has generated substantial clinical data attesting to the efficacy of epigenetics as a viable approach to understand cancer progression or therapy. In this review, we look at the fundamental epigenetic principles, the changes in the epigenome which can often be a precursor to cancer, analyse the increasingly important role of epigenetics in decoding carcinogenesis, explore the latest advancements in use of epigenetics in cancer therapy and how the reversible nature of these epigenetic changes have changed the way we approach cancer therapy.

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“…In 12 cases for whom tumor data were available, no deletions or mutations within the remaining RECQL4 allele were detected. Although other mechanisms might account for a second hit (e.g., changes in methylation) (Mazor et al 2015; Di Ruscio et al 2016), it remains possible that RECQL4 haploinsufficiency, perhaps in combination with other oncogenic events, is enough to promote malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma

Maciaszek

Oak

Hamilton

et al. 2019

Cold Spring Harb Mol Case Stud

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Patients harboring germline pathogenic biallelic variants in genes involved in the recognition and repair of DNA damage are known to have a substantially increased cancer risk. Emerging evidence suggests that individuals harboring heterozygous variants in these same genes may also be at heightened, albeit lesser, risk for cancer. Herein, we sought to determine whether heterozygous variants in RECQL4, the gene encoding an essential DNA helicase that is defective in children with the autosomal recessive cancer-predisposing condition Rothmund–Thomson syndrome (RTS), are associated with increased risk for childhood cancer. To address this question, we interrogated germline sequence data from 4435 pediatric cancer patients at St. Jude Children's Research Hospital and 1127 from the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and identified 24 (0.43%) who harbored loss-of-function (LOF) RECQL4 variants, including five of 249 (2.0%) with osteosarcoma (OS). These RECQL4 variants were significantly overrepresented in children with OS, the cancer most frequently observed in patients with RTS, as compared to 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = 0.00087, odds ratio [OR] = 7.1, 95% CI, 2.9–17). Nine of the 24 (38%) individuals possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis. Altogether these data expand our understanding of the genetic factors predisposing to childhood cancer and reveal a novel association between heterozygous RECQL4 LOF variants and development of pediatric OS.

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The second hit of DNA methylation

Cited by 8 publications

References 9 publications

Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome

Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome

Epigenetics and Cancer: A Comprehensive Review

Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma

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