Epigenetic Influences in the Aetiology of Cancers Arising from Breast and Prostate: A Hypothesised Transgenerational Evolution in Chromatin Accessibility

Abstract

Epidemiological studies have consistently supported the notion that environmental and/or dietary factors play a central role in the aetiology of cancers of the breast and prostate. However, for more than five decades investigators have failed to identify a single cause-and-effect factor, which could be implicated; identification of a causative entity would allow the implementation of an intervention strategy in at-risk populations. This suggests a more complex pathoaetiology for these cancer sites, compared to others. When one examines the increases or decreases in incidence of specific cancers amongst migrant populations, it is notable that disease arising in colon or stomach requires one or at most two generations to exhibit a change in incidence to match that of high-incidence regions, whereas for breast or prostate cancer, at least three generations are required. This generational threshold could suggest a requirement for nonmutation-driven epigenetic alterations in the F0/F1 generations (parental/offspring adopting a more westernized lifestyle), which then predisposes the inherited genome of subsequent generations to mutagenic/genotoxic alterations leading to the development of sporadic cancer in these target sites. As such, individual susceptibility to carcinogen insult would not be based per se on polymorphisms in activating/detoxifying/repair enzymes, but on elevated accessibility of crucial target genes (e.g., oncogenes, tumour suppressor genes) or hotspots therein to mutation events. This could be termed a genomic susceptibility organizational structure (SOS). Several exposures including alcohol and heavy metals are epigens (i.e., modifiers of the epigenome), whereas others are mutagenic/genotoxic, for example, heterocyclic aromatic amines; humans are continuously and variously exposed to mixtures of these agents. Within such a transgenerational multistage model of cancer development, determining the interaction between epigenetic modification to generate a genomic SOS and genotoxic insult will facilitate a new level of understanding in the aetiology of cancer.

Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G Variations in Breast Carcinoma

“…Epigenetic alterations in cancer-related genes are recognized to play an important role in BC carcinogenesis. Epidemiological studies have consistently supported that cancer is related not only to mutations in functional genes but also related to the aberrant epigenetic modifications of various genes (Chang and Sharan, 2012;Jeong et al, 2013;Martin, 2013;Zheng et al, 2013). Altered DNA methylation profiles play crucial role in miRNAs process and this are important regulators of gene expression that are frequently deregulated in cancer.…”

Environmental chemical stressors as epigenome modifiers: a new horizon in assessment of toxicological effects

“…Particular gene expression profiles can pre-dispose both parental and subsequent generations to an elevated susceptibility to disease [10]. Therefore, these stressors very probably modulate disease susceptibility.…”

“…Whilst one inherits their genetic sequence code, the expression or silencing of individual genes can be modified by environmental factors [10,17]. Recent research suggests that exposure to environmental stressors, including nutritional factors and chemical or physical pollutants can alter gene expression via altered epigenetic components [18][19][20][21][22].…”

“…Several additional classes of ncRNAs, such as repeatassociated small-interfering (si) RNAs (RasiRNAs) in Drosophila and their mammalian counterparts Piwi protein-interacting RNAs (piRNAs), are found to be involved in the regulation of genomic architecture, the maintenance of germline genomic integrity and the ageing process [7,8]. Moreover, as parental imprinting is intimately linked to ncRNAs [8], this reflects the fact that RNA-directed regulatory processes may also transfer epigenetic information not only within cells but also between cells and organ systems, as well as being trans-generational [10]. Recent research suggests LINE-1 retrotransposon RNA is an essential structural and functional epigenetic component for centromeric activity [11] and non-coding genes Xist (Xinactive specific transcript), an RNA gene on the X chromosome of placental mammals that acts as an effector of the X-inactivation process, can regulate the expansion of heterochromatin [12].…”

Prostate Cancer Epigenome

“…More recently, the concept of generational threshold in prostate cancer incidence is also gaining attention. Prostate cancer risk is usually low in recently migrated populations but within three generations, the risk of prostate cancer among these migrant populations is almost similar to or higher than the native host country population [33]. This generational threshold appears in part due to epigenetic alterations (parental/offspring adopting a more westernized lifestyle) and not due to genetic mutations in the F0/F1 generations.…”