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Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer.

ABSTRACT: Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 841 healthy controls. Functional validation was performed for the top GWAS variant on chromosome 14q12 (rs225902, close to PRKD1). After bioinformatic annotation and in silico predictions, we performed transcript analysis in a cervical tissue series of 317 samples and demonstrate rs225902 as an expression quantitative trait locus (eQTL) for FOXG1 and two tightly co-regulated long non-coding RNAs at this genomic region, CTD-2251F13 (lnc-PRKD1-1) and CTD-2503I6 (lnc-FOXG1-6). We also show allele-specific effects of the 14q12 variants via luciferase assays. We propose a combined effect of genotype, HPV status and gene expression at this locus on cervical cancer progression. Taken together, this work uncovers a potential candidate locus with regulatory functions and contributes to the understanding of genetic susceptibility to cervical cancer.

SUBMITTER: Ramachandran D

PROVIDER: S-EPMC9396939 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer.

Ramachandran Dhanya D Dennis Joe J Fachal Laura L Schürmann Peter P Bousset Kristine K Hülse Fabienne F Mao Qianqian Q Wang Yingying Y Jentschke Matthias M Böhmer Gerd G Strauß Hans-Georg HG Hirchenhain Christine C Schmidmayr Monika M Müller Florian F Runnebaum Ingo I Hein Alexander A Stübs Frederik F Koch Martin M Ruebner Matthias M Beckmann Matthias W MW Fasching Peter A PA Luyten Alexander A Dürst Matthias M Hillemanns Peter P Easton Douglas F DF Dörk Thilo T

Human molecular genetics 20220801 15

Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 8 ...[more]

PMID: 35157032

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Project description:Aims/hypothesisBy genome-wide association meta-analysis, 17 genetic loci associated with fasting serum insulin (FSI), a marker of systemic insulin resistance, have been identified. To define potential culprit genes in these loci, in a cross-sectional study we analysed white adipose tissue (WAT) expression of 120 genes in these loci in relation to systemic and adipose tissue variables, and functionally evaluated genes demonstrating genotype-specific expression in WAT (eQTLs).MethodsAbdominal subcutaneous adipose tissue biopsies were obtained from 114 women. Basal lipolytic activity was measured as glycerol release from adipose tissue explants. Adipocytes were isolated and insulin-stimulated incorporation of radiolabelled glucose into lipids was used to quantify adipocyte insulin sensitivity. Small interfering RNA-mediated knockout in human mesenchymal stem cells was used for functional evaluation of genes.ResultsAdipose expression of 48 of the studied candidate genes associated significantly with FSI, whereas expression of 24, 17 and 2 genes, respectively, associated with adipocyte insulin sensitivity, lipolysis and/or WAT morphology (i.e. fat cell size relative to total body fat mass). Four genetic loci contained eQTLs. In one chromosome 4 locus (rs3822072), the FSI-increasing allele associated with lower FAM13A expression and FAM13A expression associated with a beneficial metabolic profile including decreased WAT lipolysis (regression coefficient, R = -0.50, p = 5.6 × 10-7). Knockdown of FAM13A increased lipolysis by ~1.5-fold and the expression of LIPE (encoding hormone-sensitive lipase, a rate-limiting enzyme in lipolysis). At the chromosome 7 locus (rs1167800), the FSI-increasing allele associated with lower POM121C expression. Consistent with an insulin-sensitising function, POM121C expression associated with systemic insulin sensitivity (R = -0.22, p = 2.0 × 10-2), adipocyte insulin sensitivity (R = 0.28, p = 3.4 × 10-3) and adipose hyperplasia (R = -0.29, p = 2.6 × 10-2). POM121C knockdown decreased expression of all adipocyte-specific markers by 25-50%, suggesting that POM121C is necessary for adipogenesis.Conclusions/interpretationGene expression and adipocyte functional studies support the notion that FAM13A and POM121C control adipocyte lipolysis and adipogenesis, respectively, and might thereby be involved in genetic control of systemic insulin sensitivity.

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Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer.

Publications

Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer.

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