HSD17B7 gene in self‐renewal and oncogenicity of keratinocytes from Black versus White populations

Human populations of Black African ancestry have a relatively high risk of aggressive cancer types, including keratinocyte‐derived squamous cell carcinomas (SCCs). We show that primary keratinocytes (HKCs) from Black African (Black) versus White Caucasian (White) individuals have on average higher oncogenic and self‐renewal potential, which are inversely related to mitochondrial electron transfer chain activity and ATP and ROS production. HSD17B7 is the top‐ranked differentially expressed gene in HKCs and Head/Neck SCCs from individuals of Black African versus Caucasian ancestries, with several ancestry‐specific eQTLs linked to its expression. Mirroring the differences between Black and White HKCs, modulation of the gene, coding for an enzyme involved in sex steroid and cholesterol biosynthesis, determines HKC and SCC cell proliferation and oncogenicity as well as mitochondrial OXPHOS activity. Overall, the findings point to a targetable determinant of cancer susceptibility among different human populations, amenable to prevention and management of the disease. SYNOPSIS Differences in individuals' cancer susceptibility can be attributed, in part, to specific genetic and epigenetic variations. Human populations of Black African ancestry have a higher risk of aggressive cancer of various types, including keratinocyte‐derived squamous cell carcinomas (SCCs). Higher oncogenic and self‐renewal potential with lower mitochondrial respiratory and OXPHOS activities were observed in keratinocytes from Black African versus White Caucasian individuals. HSD17B7 was the top‐ranked differentially expressed gene in primary keratinocytes and Head/Neck SCCs from Black African versus Caucasian populations, with ancestry‐specific eQTLs linked to its expression. HSD17B7 codes for a targetable enzyme involved in sex steroid and cholesterol biosynthesis. HSD17B7 was found to play a key role in control of keratinocyte stem cell and oncogenic potential as well as mitochondrial OXPHOS activity. Graphical Abstract Differences in individuals' cancer susceptibility can be attributed, in part, to specific genetic and epigenetic variations. Human populations of Black African ancestry have a higher risk of aggressive cancer of various types, including keratinocyte‐derived squamous cell carcinomas (SCCs).