title: High-level of viral genomic diversity in cervical cancers: A Brazilian study on human papillomavirus type 16.
abstract: Invasive cervical cancer (ICC) is the third most frequent cancer among women worldwide and is associated with persistent infection by carcinogenic human papillomaviruses (HPVs). The combination of large populations of viral progeny and decades of sustained infection may allow for the generation of intra-patient diversity, in spite of the assumedly low mutation rates of PVs. While the natural history of chronic HPVs infections has been comprehensively described, within-host viral diversity remains largely unexplored. In this study we have applied next generation sequencing to the analysis of intra-host genetic diversity in ten ICC and one condyloma cases associated to single HPV16 infection. We retrieved from all cases near full-length genomic sequences. All samples analyzed contained polymorphic sites, ranging from 3 to 125 polymorphic positions per genome, and the median probability of a viral genome picked at random to be identical to the consensus sequence in the lesion was only 40%. We have also identified two independent putative duplication events in two samples, spanning the L2 and the L1 gene, respectively. Finally, we have identified with good support a chimera of human and viral DNA. We propose that viral diversity generated during HPVs chronic infection may be fueled by innate and adaptive immune pressures. Further research will be needed to understand the dynamics of viral DNA variability, differentially in benign and malignant lesions, as well as in tissues with differential intensity of immune surveillance. Finally, the impact of intralesion viral diversity on the long-term oncogenic potential may deserve closer attention.
authors.affiliation: Laboratório de Virologia, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil; Infections and Cancer Laboratory, Catalan Institute of Oncology, Barcelona, Spain. Electronic address: cristina.oliveira1@gmail.com.
authors.forename: Cristina Mendes
authors.initials: CM
authors.lastname: de Oliveira
authors.affiliation: Infections and Cancer Laboratory, Catalan Institute of Oncology, Barcelona, Spain.
authors.forename: Ignacio G
authors.initials: IG
authors.lastname: Bravo
authors.affiliation: Laboratório de Virologia, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Nathália Caroline
authors.initials: NC
authors.lastname: Santiago e Souza
authors.affiliation: Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina, São Paulo, Brazil.
authors.forename: Maria Luiza Nogueira Dias
authors.initials: ML
authors.lastname: Genta
authors.affiliation: Teaching and Research Institute, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
authors.forename: José Humberto Tavares Guerreiro
authors.initials: JH
authors.lastname: Fregnani
authors.affiliation: Gynecology Department, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Maricy
authors.initials: M
authors.lastname: Tacla
authors.affiliation: Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina, São Paulo, Brazil.
authors.forename: Jesus Paula
authors.initials: JP
authors.lastname: Carvalho
authors.affiliation: Molecular Oncology Research Center, Hospital de Câncer de Barretos, Barretos, São Paulo, Brazil; Laboratory of Medical Investigation (LIM) 14, Faculty of Medicine, University of São Paulo, São Paulo, Brazil; Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Adhemar
authors.initials: A
authors.lastname: Longatto-Filho
authors.affiliation: Laboratório de Virologia, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: José Eduardo
authors.initials: JE
authors.lastname: Levi
mesh_terms: D000230:Adenocarcinoma / Q000821:virology*; D000328:Adult; D000368:Aged; D001938:Brazil; D002294:Carcinoma, Squamous Cell / Q000821:virology*; D005260:Female; D014644:Genetic Variation; D016679:Genome, Viral; D059014:High-Throughput Nucleotide Sequencing; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology*; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D002583:Uterine Cervical Neoplasms / Q000821:virology*
keywords: Cervical cancer; HPV16 diversity; Intralesion