RESUMEN
Persistent high-risk human papillomavirus (HR-HPV) infections play a major role in the development of invasive cervical cancer (CC), and screening for such infections is in many countries the primary method of detecting and preventing CC. HPV typing can be used for triage and risk stratification of women with atypical squamous cells of undetermined significance (ASC-US)/low-grade cervical lesions (LSIL), though the current clinical practice in Mexico is to diagnose CC or its preceding conditions mainly via histology and HR-HPV detection. Additional information regarding these HPV infections, such as viral load and co-infecting agents, might also be useful for diagnosing, predicting, and evaluating the possible consequences of the infection and of its prevention by vaccination. The goal of this follow-up hospital case study was to determine if HPV types, multiple HPV infections, and viral loads were associated with infection persistence and the cervical lesion grade. A total of 294 cervical cytology samples drawn from patients with gynecological alterations were used in this study. HPV types were identified by real-time PCR DNA analysis. A subset of HPV-positive patients was reevaluated to identify persistent infections. We identified HPV types 16, 18, and 39 as the most prevalent. One hundred five of the patients (59%) were infected with more than one type of HPV. The types of HPV associated with multiple HPV infections were 16, 18, and 39. In the follow-up samples, 38% of patients had not cleared the initially detected HPV infection, and these were considered persistent. We found here an association between multiple HPV infections and high viral loads with and infection persistence. Our findings suggest there are benefits in ascertaining viral load and multiple HPV infections status of HR-HPV infections for predicting the risk of persistence, a requirement for developing CC. These findings contribute to our understanding of HPV epidemiology and may allow screening programs to better assess the cancer-developing risks associated with individual HR-HPV infections.
Asunto(s)
Coinfección/virología , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/virología , Carga Viral , Adulto , Coinfección/epidemiología , Coinfección/patología , ADN Viral/genética , Femenino , Estudios de Seguimiento , Genotipo , Humanos , México/epidemiología , Prueba de Papanicolaou , Papillomaviridae/clasificación , Papillomaviridae/genética , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/patología , Prevalencia , Frotis VaginalRESUMEN
Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.
Asunto(s)
Genoma Humano/genética , Mutación/genética , Neoplasias del Cuello Uterino/genética , Adenocarcinoma/genética , Adenocarcinoma/virología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Proteína p300 Asociada a E1A/genética , Exoma/genética , Proteínas F-Box/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Genómica , Antígenos HLA-B/genética , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Factor 2 Relacionado con NF-E2/genética , Papillomaviridae/genética , Papillomaviridae/fisiología , Infecciones por Papillomavirus/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , Receptor ErbB-2/genética , Factores de Transcripción/genética , Transcriptoma/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Neoplasias del Cuello Uterino/virología , Integración Viral/genéticaRESUMEN
BACKGROUND: Persistent infection with high-risk human papillomavirus (HPV) is a major risk factor for malignant lesions and cervical cancer. A widely studied element in the search for genetic factors influencing risk HPV infection diseases is allelic variation of the human leukocyte antigen (HLA) locus. The study was designed to search for HLA susceptibility alleles contributing to the persistence of HPV infection in Mexican women. METHODS: A total of 172 subjects were divided into three groups: 1) HPV-persistent patients; 2) HPV-cleared; and 3) HPV-reinfected patients. They were screened for HPV types using a polymerase chain reaction (PCR). PCR-sequence specific oligonucleotide probes (PCR-SSOP) was used for HLA DRB1 and DQB1 typing. RESULTS: We observed that HLA-DQB1*0501 allele might be associated with susceptibility of reinfection with HPV (p = 0.01, OR = 4.9, CI 95% = 1.3 -18.7). Allele frequency of HLA-DRB1*14 was particularly reduced in patients with cancer when compared with the HPV-persistent group (p = 0.04), suggesting that this allele is a possible protective factor for the development of cervical cancer (OR = 2.98). HLA-DRB1*07 might be associated with viral clearance (p = 0.04). CONCLUSIONS: Genetic markers for HPV infection susceptibility are different in each population, in Mexicans several HLA-DQB1 alleles might be associated with an enhanced risk for viral persistence. In contrast, DRB1*14, seems to confer protection against cervical cancer.
