Different Association of Human Papillomavirus 16 Variants with Early and Late Presentation of Cervical Cancer

Abstract

The median age of cervical cancer (CC) presentation coincides with the mean age of menopause presentation (49 years) in Mexico. Here, we investigated the association between different HPV16 variants and early (≤ 49 years) or delayed (≥ 50 years) CC presentation. We conducted a case-case study that included 462 CCs, 386 squamous cell carcinomas (SCC), 63 adenocarcinomas (ACC), and 13 additional cell types. Variants were identified by PCR and DNA sequencing. The risk conferred by each variant for developing CC earlier than 50 years was analyzed using a univariate logistic regression model considering old-aged patients (≥ 50 years) and non-HPV16 cases as the reference variables. Overall, the frequency of HPV16 was 50.9%, and the only identified variants were the European A1/2 (31.2%) and the Asian-American D2 (10.8%), and D3 (8.9%). D2 was mainly associated with ≤ 49-year-old patients (15.9%); A1/2 was uniformly distributed between the two age groups (~31%), whereas D3 increased with age to a frequency of 11.8% in the older group. Only the D2 variant conferred a 3.3-fold increase in the risk of developing CC before 50 years of age (OR = 3.3, 95% CI = 1.7–6.6, p < 0.001) in relation with non-HPV16 cases. Remarkably, this risk was higher for ACC (OR = 6.0, 95% CI = 1.1–33, p < 0.05) than for SCC (OR = 2.8, 95% CI = 1.3–5.9, p < 0.01). Interestingly, when analyzing only the HPV16-positive CC, D2 increases (OR = 2.5, 95% CI = 1.2–5, p < 0.05) and D3 decreases (OR = 0.45, 95% CI 0.2–0.9, p < 0.05) the risk to develop CC before 50 years old in relation with A1/2 variant. These results indicated that D2 variant is associated with early and D3 with delayed CC presentation, whereas A1/2 variant was uniformly distributed between the two age groups.

High frequency of HPV16 European variant E350G among Mexican women from Sinaloa

“…This result was similar to previous reports of this genotype in asymptomatic populations elsewhere in the world and consistent with other studies conducted in Mexico 13 21 . The frequency was lower than that reported in Mexican patients with CC in whom the frequency of HPV16 was 50.9 per cent 14 .…”

“…The sequence variations in the HPV16 E6 gene have been observed to correctly classify HPV16 variants isolated from different continents 11 . Therefore, most studies of HPV16 variants have focused on the E6 gene, which encodes the major transforming protein that inhibits apoptosis, promotes cellular proliferation and is associated with cancer aggressiveness 12 13 14 . Worldwide, variants of the HPV16 genome in CC from different geographical areas have been classified into phylogenetic lineages, such as European (E) (A1-A4), Asian (As), Asian-America (AA) (D2 and D3), African-1 and -2 (Af1 and Af2) (B1, B2 and C) and North American (NA1) (D1) 14 .…”

“…Therefore, most studies of HPV16 variants have focused on the E6 gene, which encodes the major transforming protein that inhibits apoptosis, promotes cellular proliferation and is associated with cancer aggressiveness 12 13 14 . Worldwide, variants of the HPV16 genome in CC from different geographical areas have been classified into phylogenetic lineages, such as European (E) (A1-A4), Asian (As), Asian-America (AA) (D2 and D3), African-1 and -2 (Af1 and Af2) (B1, B2 and C) and North American (NA1) (D1) 14 . Some studies have shown that HPV16 variants promote disease progression, ranging from HG-SIL to the development of CC 14 15 .…”

“…Worldwide, variants of the HPV16 genome in CC from different geographical areas have been classified into phylogenetic lineages, such as European (E) (A1-A4), Asian (As), Asian-America (AA) (D2 and D3), African-1 and -2 (Af1 and Af2) (B1, B2 and C) and North American (NA1) (D1) 14 . Some studies have shown that HPV16 variants promote disease progression, ranging from HG-SIL to the development of CC 14 15 . In a previous study based on all 47 sequenced HPV16 genomes, the European variant nt350G was observed to occur frequently in HG-SIL [odds ratio (OR)=3.8, P =0.03], and was present in 36 HPV16 isolates from women with minor cervical abnormalities (OR=4.8, P =0.07) 16 .…”

Role of HPV 16 variants among cervical samples from Northeastern Brazil

“…In a study by Alfaro et al, (2016) [26] of 462 women with cervical cancer, HPV 16 was identified in 50.9% of the cases. Of these, the A1\2 (31.4%) sublineage was predominant, followed by the D2 (10.4%) and D3 (9.1%) sublineages.…”