Human papillomavirus 16 positive cervical cancer in Guatemala: The D2 and D3 sublineages differ in integration rate and age of diagnosis

Abstract

Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, D) have been described, as well as multiple sub-lineages. To identify molecular events associated with HPV16 carcinogenesis we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 64% (60/94) of the samples had integrated HPV16 sequences, and integration was associated with an earlier age of diagnosis (P=0.0007) and pre-menopausal disease. HPV16 integration sites were broadly distributed in the genome but in one tumor, HPV16 integrated into the promoter of the interferon regulatory factor 4 (IRF4) gene, which plays an important role in the regulation of the interferon response to viral infection. The HPV16 D2 and D3 sub-lineages were found in 23% and 30% of the tumors, respectively and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration (P=0.011), earlier age of diagnosis (P=0.012), and a lower rate of somatic mutation (P=0.03). Whereas D3-positive tumors are less likely to integrate, have later age-of-diagnosis, and a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of the very high-risk HPV16 D2 and D3 sub-lineages and cervical cancer patients with these variants of HPV16 differ in histology, age of-diagnosis, integration, and somatic mutation frequency. In summary, related lineages of HPV16 have different features of oncogenicity.

História natural da infecção por variantes genéticas de HPV-16 no canal anal de homens participantes do estudo internacional multicêntrico HIM (HPV Infection in Men)

“…We, and others, have previously demonstrated that, among multiethnic populations, HPV-16 infections with lineage D and sublineage A4 variants confer increased risk for cervical infection persistence and lesion development (Berumen et al, 2001;Hildesheim et al, 2001;Mirabello et al, 2016;Sichero et al, 2007). Specific HPV-16 variants seem also to be associated with histopathological features of cervical tumors, where variants of sublineages A1-A3 are associated only to squamous cell carcinomas (SCC), and those of lineage D are associated with both SCC and adenocarcinomas (ADC), which are often more aggressive than SCC (Berumen et al, 2001;Lou et al, 2020;Mirabello et al, 2016). A summary of tumor vs. nontumor samples may be found in Table 3.…”

“…Several studies have shown that HPV-16 lineage D variants are associated with a higher risk of infection persistence and cervical cancer development (Sichero et al, 2007;Xi et al, 2007;Mirabello et al, 2016) mostly within populations with a multiethnic composition. In addition, higher rates of integration are observed for lineage D variants compared to other HPV-16 variants (Lou et al, 2020). However, this relationship in male-associated anogenital cancers is, by far, less reported.…”