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. 2023 Sep 1;32(9):1190-1197.
doi: 10.1158/1055-9965.EPI-23-0300.

Variations in Genes Encoding Human Papillomavirus Binding Receptors and Susceptibility to Cervical Precancer

Amrita Mukherjee  1 , Yuanfan Ye  1 , Howard W Wiener  1 , Mark H Kuniholm  2 , Howard Minkoff  3 , Kate Michel  4 , Joel Palefsky  5 , Gypsyamber D'Souza  6 , Lisa Rahangdale  7 , Kenneth R Butler  8 , Mirjam-Colette Kempf  1   9 , Staci L Sudenga  10 , Bradley E Aouizerat  11 , Akinyemi I Ojesina  1 , Sadeep Shrestha  1
Affiliations

Variations in Genes Encoding Human Papillomavirus Binding Receptors and Susceptibility to Cervical Precancer

Amrita Mukherjee et al. Cancer Epidemiol Biomarkers Prev. .

Abstract

Background: Cervical cancer oncogenesis starts with human papillomavirus (HPV) cell entry after binding to host cell surface receptors; however, the mechanism is not fully known. We examined polymorphisms in receptor genes hypothesized to be necessary for HPV cell entry and assessed their associations with clinical progression to precancer.

Methods: African American women (N = 1,728) from the MACS/WIHS Combined Cohort Study were included. Two case-control study designs were used-cases with histology-based precancer (CIN3+) and controls without; and cases with cytology-based precancer [high-grade squamous intraepithelial lesions (HSIL)] and controls without. SNPs in candidate genes (SDC1, SDC2, SDC3, SDC4, GPC1, GPC2, GPC3, GPC4, GPC5, GPC6, and ITGA6) were genotyped using an Illumina Omni2.5-quad beadchip. Logistic regression was used to assess the associations in all participants and by HPV genotypes, after adjusting for age, human immunodeficiency virus serostatus, CD4 T cells, and three principal components for ancestry.

Results: Minor alleles in SNPs rs77122854 (SDC3), rs73971695, rs79336862 (ITGA6), rs57528020, rs201337456, rs11987725 (SDC2), rs115880588, rs115738853, and rs9301825 (GPC5) were associated with increased odds of both CIN3+ and HSIL, whereas, rs35927186 (GPC5) was found to decrease the odds for both outcomes (P value ≤ 0.01). Among those infected with Alpha-9 HPV types, rs722377 (SDC3), rs16860468, rs2356798 (ITGA6), rs11987725 (SDC2), and rs3848051 (GPC5) were associated with increased odds of both precancer outcomes.

Conclusions: Polymorphisms in genes that encode binding receptors for HPV cell entry may play a role in cervical precancer progression.

Impact: Our findings are hypothesis generating and support further exploration of mechanisms of HPV entry genes that may help prevent progression to cervical precancer.

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Figures

Figure 1. Schematic illustrations of HSPGs involvement as co-receptors in early stage of HPV cell entry. 1. HSPG is suggested as the primary receptor for HPV cell entry. L1 capsid protein binds to HSPG GAG chains. Heparan sulfate is mostly found on two membrane-bound proteoglycans – syndecans and glypicans; 2. Interaction of capsid with CyPB results in conformational changes in L1 and L2. This is followed by furin cleavage of L2 and increased affinity to secondary receptors; 3. Furin cleavage of L2 triggers actin-dependent receptors. (Created with BioRender.com)
Figure 1.
Schematic illustrations of HSPGs involvement as co-receptors in early stage of HPV cell entry. 1. HSPG is suggested as the primary receptor for HPV cell entry. L1 capsid protein binds to HSPG GAG chains. Heparan sulfate is mostly found on two membrane-bound proteoglycans – syndecans and glypicans; 2. Interaction of capsid with CyPB results in conformational changes in L1 and L2. This is followed by furin cleavage of L2 and increased affinity to secondary receptors; 3. Furin cleavage of L2 triggers actin-dependent receptors. (Created with BioRender.com)
Figure 2. Forest plot showing the individual association (aOR and 95% CI) between genetic variants and both CIN3+ and HSIL as outcome endpoints for cervical precancer (adjusted for age, HIV sero-status, CD4 T-cell counts, and three principal components for genetic ancestry; SNPs with P value ≤ 0.01 are presented (before adjusting for multiple comparisons).
Figure 2.
Forest plot showing the individual association (aOR and 95% CI) between genetic variants and both CIN3+ and HSIL as outcome endpoints for cervical precancer (adjusted for age, HIV sero-status, CD4 T-cell counts, and three principal components for genetic ancestry; SNPs with P value ≤ 0.01 are presented (before adjusting for multiple comparisons).
See this image and copyright information in PMC

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