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

Xiaoying Xu,Atul Katarkar,Beatrice Tassone,Chiara Riganti,Tatiana Proust,Zoltan Kutalik,Jean‐Marc Joseph,Paola Ostano,Giovanna Chiorino,Karine Lefort,Gian Paolo Dotto

doi:10.15252/emmm.202114133

Abstract

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.

Highlights

Human populations with different genetic backgrounds differ significantly in susceptibility to many cancer types (Ozdemir & Dotto, 2017; Li et al, 2020; Zavala et al, 2021)
From which squamous cell carcinomas (SCCs) arise, we have found that cells derived from individuals of Black African versus Caucasian ancestries are generally endowed with intrinsically higher oncogenic and self-renewal potential
By focusing on keratinocytes from which squamous cell carcinomas arise, we have found that cells derived from individuals of Black African are generally endowed with intrinsically higher oncogenic and self-renewal potential than those derived from Caucasian ancestries, which are associated with lower mitochondrial oxidative phosphorylation (OXPHOS) activity and ROS production

Summary

Introduction

Human populations with different genetic backgrounds differ significantly in susceptibility to many cancer types (Ozdemir & Dotto, 2017; Li et al, 2020; Zavala et al, 2021) These differences can result from a combination of socioeconomical and behavioral factors, but disparities in cancer risk persist after normalization for these factors and in equal access settings, such as in the US Military Health System (Andaya et al, 2013; Schreiber et al, 2014; Dess et al, 2019). Whether or not there are ancestry-related differences of functional significance in normal stem cell populations from which tumors arise has not, to our knowledge, been investigated

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Conclusion