Association of HPV35 with cervical carcinogenesis among women of African ancestry: Evidence of viral-host interaction with implications for disease intervention

Abstract

HPV35 has been found in only ∼2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub-Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U.S. and internationally. Combining five U.S. studies, we measured HPV35 positivity and, in Northern California, observed HPV35 type-specific population prevalence and estimated 5-year risk of developing precancer when HPV35-positive. HPV35 genetic variation was examined for differences in carcinogenicity in 1053 HPV35+ cervical specimens from a U.S. cohort and an international collection. African-American women had more HPV35 (12.1% vs 5.1%, P < .001) and more HPV35-associated precancers (7.4% vs 2.1%, P < .001) compared to other ethnicities. Precancer risks after HPV35 infection did not vary by ethnicity (global P = .52). The HPV35 A2 sublineage showed an increased association with precancer/cancer in African-Americans (OR = 5.6 vs A1, 95% CI = 1.3-24.8) and A2 was more prevalent among ICC in Africa than other world regions (41.9% vs 10.4%, P < .01). Our analyses support a strong link between HPV35 and cervical carcinogenesis in women of African ancestry. Current HPV vaccines cover the majority of cervical precancer/cancer across all ethnic groups; additional analyses are required to determine whether the addition of HPV35 to the already highly effective nine-valent HPV vaccine would provide better protection for women in Africa or of African ancestry.

Keywords: African ancestry women; HPV35; cervical cancer; epidemiology; genetics.

FIGURE 1

Phylogenetic tree illustrating HPV35 lineages, and individual SNPs across the HPV35 genome associated with CIN3+ in African-American women. A, HPV35 complete genome tree topology. The maximum likelihood (ML) tree was constructed using RAXML from a global alignment of complete HPV35 genome nucleotide sequences from the Persistence and Progression (PaP) Cohort and IARC samples, as well as reference sequences, bootstrap support values equal to or higher than 50 are shown on or near branches. HPV31 was used as an outgroup taxon to root the tree (not shown). Distinct variant lineages (ie, termed A and B) and sublineages (eg, termed A1 and A2) were inferred from the tree topology. The bar indicates the nucleotide substitutions per unit change (ie, 0.001) per site. B, SNPs significantly associated with CIN3+ among African-American women in the PaP Cohort. Odds ratios (OR) are shown on the y-axis and HPV35 genome positions by viral gene regions are shown on the x-axis. Circles represent variants significantly (P < .05) associated with CIN3+ compared to other nucleotide at the same genomic position. For details, see Table S4

FIGURE 2

Prevalence of HPV35 among CIN2, CIN3 and cancer cases testing positive for carcinogenic HPV from 5 studies. CIN2, cervical intraepithelial neoplasia (CIN) grade 2; CIN3, CIN grade 3; WH, White; HIS, Hispanic; AS, Asian; AA, African-American. n, number of women with tested specimens. Among CIN2 and CIN3 cases, African-American women were more likely to have a “single HPV35 infection” (13.0% vs 3.5%, P < .001 for CIN2 and 5.5% vs 1.9%, P < .001 for CIN3) and both a “single HPV35 infection” and “HPV35 co-infection, most prevalent” (18.7% vs 4.2%, P < .001 for CIN2 and 7.4% vs 2.1%, P < .001 for CIN3). Differences were not statistically significant for cancers (P = .1). The number of cases from the studies presented in Table S5 and percent with 95% confidence intervals are presented in Table S2