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Genetic/epigenetic basis of ethnic differences in cancer predisposition

Final Report Summary - ECAP (Genetic/epigenetic basis of ethnic differences in cancer predisposition)

"Race" refers to a population with common genetic and phenotypic features that separate them from other populations. "Ethnicity" pertains to the different cultural, socioeconomic, religious properties, including customs, language, diet, and cultural identity. The association of race with political ideologies and the abuse of science to promote racism have rendered the term race itself problematic. This ERC-supported research project was focused on the biological basis of disparities in cancer risk among human populations with different "ancestry", which we are employing as preferable term instead of "race" or "ethnicity".
Epidemiological data point to large disparities in incidence and survival of many cancer types in human populations with different ancestries. The most comprehensive data on racial differences are derived from US cancer registries. According to these, African American populations, to whom the registries as "black", have higher incidence and lesser survival of many cancer types relative to populations of Caucasian origin, referred to as "white". These differences were historically attributed to confounding socioeconomical and behavioral factors, such as diet, alcohol abuse, smoking, and access to screening and treatment. However, there is evidence that the survival disparity persists after normalization for these factors and in equal access settings, such as in the US Military Health System. In this context, while differences in incidence of specific cancer types over the past 20 years have lessened or disappeared, the survival gap between "black" and "white" populations remained, independent of stage at diagnosis and treatment.
The biological basis of differences in cancer susceptibility among populations of different ancestries can be attributed, in part, to differences in genetic and epigenetic determinants of organismic functions such as metabolism, native and acquired immunity and drug detoxification. Our research project was guided by the hypothesis that population-specific differences in cancer stem-like cells (CSCs) of origin and surrounding stromal cells can play an equally important or primary role in initiation and progression of the disease, focusing on squamous cell carcinoma (SCC), the most common type of solid human cancer that develops at the surface of the skin as well as many internal organs, such the oral cavity and esophagus, bronchial tree and lung, and the cervix.
The skin provides a unique resource for relatively large-scale studies of normal and cancer tissues, as these are routinely discarded at the end of surgical procedures. Growth/differentiation and self-renewal properties of epithelial cells covering the surface of the skin, named "keratinocytes", are shared with those of internal stratified epithelial tissues. We have shown that epithelial cancers that arise from all these tissues, the SCCs, have common genetic and epigenetic alterations of functional significance that can be targeted to suppress development of this cancer type. Within this context, we have found that entirely normal keratinocytes freshly derived from foreskin of young boys of Black versus versus White ancestries, have on average higher proliferative and tumorigenic potential, associated with differential metabolic activity, which we have linked to differences in energy production by specific cellular organelles, the mitochondria, and, behind that, a single specific gene, HSD17B7. The latter codes for an enzyme involved in cholesterol synthesis as well as sex hormones production and which can be targeted by a specific pharmacological inhibitor.
In a parallel line of work, we have also established that resident stromal cells in the skin, called "dermal fibroblasts", can play a key role in triggering SCC cancer development and identified molecular targets that can be targeted to prevent this process. In this context, we have also found significant functional and biochemical differences between dermal fibroblasts derived from young boys of Black versus versus White ancestries, which may lead to the identification of targets to prevent / revert the cancer process.