CRISTINA MENDES DE OLIVEIRA
Projetos de Pesquisa
Unidades Organizacionais
LIM/52 - Laboratório de Virologia, Hospital das Clínicas, Faculdade de Medicina
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- Clinical characteristics of women diagnosed with carcinoma who tested positive for cervical and anal high-risk human papillomavirus DNA and E6 RNA(2015) VEO, Carlos A. R.; SAAD, Sarhan S.; FREGNANI, Jose Humberto T. G.; SCAPULATEMPO-NETO, Cristovam; TSUNODA, Audrey Tieko; RESENDE, Julio Cesar Possati; LORENZI, Adriana Tarla; MAFRA, Allini; CINTI, Claudia; COTRIM, Ismael Dale; ROSA, Luciana Albina Reis; OLIVEIRA, Cristina Mendes de; MARTINS, Toni Ricardo; CENTRONE, Cristiane; LEVI, Jose Eduardo; LONGATTO-FILHO, AdhemarHigh-risk human papillomavirus (hrHPV) is an essential cause of cervical carcinoma and is also strongly related to anal cancer development. The hrHPV E6 oncoprotein plays a major role in carcinogenesis. We aimed to evaluate the frequency of hrHPV DNA and E6 oncoprotein in the anuses of women with cervical carcinoma. We analyzed 117 women with cervical cancer and 103 controls for hrHPV and the E6 oncogene. Positive test results for a cervical carcinoma included 66.7 % with hrHPV-16 and 7.7 % with hrHPV-18. One case tested positive for both HPV variants (0.9 %). The samples from the anal canal were positive for HPV-16 in 59.8 % of the cases. Simultaneous presence of HPV in the cervix and anal canal was found in 53.8 % of the cases. Regarding expression of E6 RNA, positivity for HPV-16 in the anal canal was found in 21.2 % of the cases, positivity for HPV-16 in the cervix was found in 75.0 %, and positivity for HPV-18 in the cervix was found in 1.9 %. E6 expression in both the cervix and anal canal was found in 19.2 % of the cases. In the controls, 1 % tested positive for HPV-16 and 0 % for HPV-18. Anal samples from the controls showed a hrHPV frequency of 4.9 % (only HPV16). The presence of hrHPV in the anal canal of women with cervical cancer was detected at a high frequency. We also detected E6 RNA expression in the anal canal of women with cervical cancer, suggesting that these women are at risk for anal hrHPV infection.
- Low mutation percentage of KRAS and BRAF genes in Brazilian anal tumors(2016) BIDINOTTO, Lucas Tadeu; VEO, Carlos A. R.; LOAIZA, Edgar Aleman; FRANCA, Alessandra Paulino Santos De; LORENZI, Adriana Tarla; ROSA, Luciana Albina Reis; OLIVEIRA, Cristina Mendes De; LEVI, Jose Eduardo; SCAPULATEMPO-NETO, Cristovam; LONGATTO-FILHO, Adhemar; REIS, Rui ManuelAnal cancer is a rare type of digestive tract disease, which has had a crescent incidence in a number of regions. Carcinomas are most frequently found, with squamous cell carcinoma (SCC) comprising similar to 95% of all anal tumors. The major risk factor for development of this type of tumor is human papillomavirus (HPV) infection. However, previous studies have identified patients with anal cancer that are HPV-/p16-and observed that they have a poorer outcome compared with HPV+/p16+ patients. This suggests that molecular profile may drive anal cancer progression. The aim of the present study was to evaluate the mutational status of two important oncogenes, KRAS and BRAF, in a series of anal cancer lesions. Resected tumors of the anal canal (n=43) were evaluated, nine of these were high-grade squamous intra-epithelial lesion cases (HSIL), 11 were adenocarcinomas, and 23 SCCs. Direct sequencing of KRAS proto-oncogene, GTPase (KRAS; codons 12 and 13) and B-Raf proto-oncogene, serine/threonine kinase (BRAF; codon 600) was performed and associated with patient clinicopathological and molecular features. There was a trend of poorer prognosis of adenocarcinoma compared with HSIL and SCC. Analysis indicated one SCC patient (2.3%) exhibited a KRAS p.G13D mutation, and one adenocarcinoma patient (2.3%) exhibited a BRAF p.V600E mutation. It was observed that, these mutations are rare in anal tumors, and certain patients may be at a disadvantage using targeted therapies based on KRAS and BRAF mutational status. As there is a low mutation percentage in SCCs, adenocarcinomas and HSIL, there may exist other underlying molecular alterations that result in anal cancer development, which require further elucidation.
- Characterization of topoisomerase II alpha and minichromosome maintenance protein 2 expression in anal carcinoma(2017) SCAPULATEMPO-NETO, Cristovam; VEO, Carlos; FREGNANI, Jose Humberto T. G.; LORENZI, Adriana; MAFRA, Allini; MELANI, Armando G. F.; LOAIZA, Edgar Antonio Aleman; ROSA, Luciana Albina Reis; OLIVEIRA, Cristina Mendes De; LEVI, Jose Eduardo; LONGATTO-FILHO, AdhemarThe present study aimed to ascertain the significance of topoisomerase II alpha (TOP2A) and minichromosome maintenance protein (MCM) 2 expression in anal carcinoma. A total of 75 anal lesions were retrieved from the files of the Department of Pathology of Barretos Cancer Hospital (Barretos, Brazil) in order to verify the human papillomavirus (HPV) statuses of these lesions and characterize the immunohistochemical expression levels of TOP2A and MCM2 in anal carcinoma, as these are important markers for cervical HPV-induced lesions; their expression was also compared with respect to p16 and Ki-67. The vast majority of the cases tested positive for HPV16 (84%); 1 case tested positive for both HPV16 and HPV18. Positive HPV16 status was more frequent in early stages than in advanced stages (P=0.008). Positive immunohistochemical reactivity for MCM2 and TOP2A protein was observed in 71.6 and 100% of cases, respectively. Positive reactivity for p16 was significantly associated (P=0.001) with histological grade, and was more commonly expressed in squamous cell carcinoma than adenocarcinomas. HPV16 was strongly associated with positive p16 protein expression (76.6%). However, the high expression of Ki-67 combined with the high expression of p16 was predominantly observed in Stage III-IV cases. MCM2, TOP2A, p16 and Ki-67 exhibited intense positive staining in the anal lesions, indicating that these markers were significantly and constantly expressed in anal carcinoma.
- HPV genotype distribution in Brazilian women with and without cervical lesions: correlation to cytological data(2016) MARTINS, Toni Ricardo; OLIVEIRA, Cristina Mendes de; ROSA, Luciana Reis; CENTRONE, Cristiane de Campos; RODRIGUES, Celia Luiza Regina; VILLA, Luisa Lina; LEVI, Jose EduardoBackground: Human Papillomavirus (HPV) genotype distribution varies according to the method of assessment and population groups. This study analyzed type-specific HPV infections among women ranging from 14-95 years old, displaying normal and abnormal cytology, from Sao Paulo and Barretos cities, Brazil. Methods: Women found positive for High Risk-HPVs DNA by either the Hybrid Capture 2 (HC2) or Cobas HPV Test (n = 431) plus a random sample of 223 negative by both assays and 11 samples with indeterminate results, totalizing 665 samples, were submitted to HPV detection by the PapilloCheck test. Cytological distribution included 499 women with a cytological result of Negative for Intraepithelial Lesion or Malignancy and 166 with some abnormality as follows: 54 Atypical Squamous Cells of Undetermined Significance; 66 Low-Grade Squamous Intraepithelial Lesion; 43 High-Grade Squamous Intraepithelial Lesion and 3 (0.5 %) Invasive Cervical Cancer. Results: From the 323 samples (48.6 %) that had detectable HPV-DNA by the PapilloCheck assay, 31 were HPV negative by the cobas HPV and HC2 assays. Out of these 31 samples, 14 were associated with HR-HPVs types while the remaining 17 harbored exclusively low-risk HPVs. In contrast, 49 samples positive by cobas HPV and HC 2 methods tested negative by the PapilloCheck assay (19.8 %). Overall, the most frequent HR-HPV type was HPV 16 (23.2 %), followed by 56 (21.0 %), 52 (8.7 %) and 31 (7.7 %) and the most frequent LR-HPV type was HPV 42 (12.1 %) followed by 6 (6.2 %). Among the HR-HPV types, HPV 56 and 16 were the most frequent types in NILM, found in 19. 1 and 17.7 % of the patients respectively while in HSIL and ICC cases, HPV 16 was the predominant type, detected in 37.2 and 66.7 % of these samples. Conclusions: In the population studied, HPV 16 and 56 were the most frequently detected HR-HPV types. HPV 56 was found mainly in LSIL and NILM suggesting a low oncogenic potential. HPV 16 continues to be the most prevalent type in high-grade lesions whereas HPV 18 was found in a low frequency both in NILM and abnormal smears. Surveillance of HPV infections by molecular methods is an important tool for the development and improvement of prevention strategies.
- Self-sampling coupled to the detection of HPV 16 and 18 E6 protein: A promising option for detection of cervical malignancies in remote areas(2018) TORRES, Katia Luz; MARINO, Josiane Montanho; ROCHA, Danielle Albuquerque Pires; MELLO, Monica Bandeira de; FARAH, Heydy Halanna de Melo; REIS, Renato dos Santos; ALVES, Valquiria do Carmo Rodrigues; GOMES, Edson; MARTINS, Toni Ricardo; SOARES, Ana Carolina; OLIVEIRE, Cristina Mendes de; LEVI, Jose EduardoObjective To evaluate both the performance and acceptability of a method coupling self-sampling with detection of cervical malignancy via elevated HPV 16 and 18 E6 oncoproteins (OncoE6((TM)) Cervical Test) in remote areas in Brazil. Methods Women living in rural villages in proximity to Coari city, Amazonas, Brazil were invited to participate in a cervical cancer screening study. 412 subjects were enrolled; there were no refusals. In addition to E6 protein detection, DNA was extracted from the brushes and evaluated for HPV genotypes by PCR (PGMY09/11), followed by typing by the Papillocheck (TM) if positive. Subjects who were found to be positive for OncoE6 or HPV-DNA were referred for colposcopy. Results For 110 subjects (27%) this was the first cervical cancer exam. Overall the HPV-DNA prevalence was 19.1% (n = 79); 1.4% (n = 6) were positive by the OncoE6 Test. Fifty-six women attended the invitation for colposcopy where nine had an abnormal cervix and were subsequently biopsied. Histopathological analysis revealed 2 CIN3, 2 carcinomas and 5 CIN1. OncoE6 called two out of the three HPV 16 or 18 associated CIN3+ lesions. Conclusions The findings suggest that self-administered sample collection in combination with OncoE6 Test is feasible in this population. This could enable expanded screening coverage while ensuring a high specificity which is imperative given the remote geographic location, since women bearing abnormal test results would necessitate travel and logistical burden to access colposcopy and treatment.
- High-level of viral genomic diversity in cervical cancers: A Brazilian study on human papillomavirus type 16(2015) OLIVEIRA, Cristina Mendes de; BRAVO, Ignacio G.; SOUZA, Nathalia Caroline Santiago e; GENTA, Maria Luiza Nogueira Dias; FREGNANI, Jose Humberto Tavares Guerreiro; TACLA, Maricy; CARVALHO, Jesus Paula; LONGATTO-FILHO, Adhemar; LEVI, Jose EduardoInvasive 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.
- The Biological Impact of Genomic Diversity in Cervical Cancer Development(2016) OLIVEIRA, Cristina Mendes de; LEVI, Jose EduardoHuman papillomaviruses (HPVs) are the etiologic agents of cervical cancer, the unique human neoplasia that has one single necessary cause. The diversity of HPVs is well described, with 200 HPV types existing as distinct taxonomic units and each receiving an Arabic number. On a clinical basis, they are usually grouped by their site of occurrence and disease associations. Those types inhabiting the anogenital mucosa are more intensively studied and further divided into cancer-associated HPVs, which are termed 'high risk', while those linked to benign proliferative lesions are assigned as 'low risk'. HPV16 is responsible for approximately 50% of all ICC cases, and paradoxically is one of the most prevalent types among healthy women. Longitudinal studies have shown that when an incidental HPV16 infection becomes persistent it will result in an enhanced risk for the development of high-grade lesions. However, it is unknown why some persistent, HPV16 infections (or infections by other HR-HPV types) progress to CIN3+ while most clear spontaneously. Several epidemiological investigations have focused on cofactors, from the most obvious such as cigarette and other carcinogenic exposures, to coinfections by other STDs such as chlamydia, with no significant findings. Thus, the current focus is on genomic variation from both virus and host. Such studies have been potentialized by the enormous technical advances in nucleic acid sequencing, allowing this relationship to be broadly interrogated. Corroborating subgenomic data from decades ago, an association between HPV16 lineages and carcinogenesis is being revealed. However, this effect does not seem to apply across female populations from different continents/ethnicities, again highlighting a role played by HPV16 adaptation and evasion from the host over time. (C) 2016 S. Karger AG, Basel.
- Loss of Raf kinase inhibitor protein expression is associated with human papillomavirus 16 infection in anal tumors(2018) BIDINOTTO, Lucas Tadeu; VEO, Carlos A. R.; LOAIZA, Edgar Aleman; RIBEIRO, Guilherme G.; LORENZI, Adriana T.; ROSA, Luciana Albina Reis; OLIVEIRA, Cristina Mendes de; LEVI, Jose Eduardo; SCAPULATEMPO-NETO, Cristovam; LONGATTO-FILHO, Adhemar; REIS, Rui ManuelThere has been an increase in the incidence of anal cancer in the past two decades, with squamous cell carcinoma (SCC) being the most frequent histological type identified. Among the risk factors, high-risk human papillomavirus (HPV) infection is the most pervasive. Raf kinase inhibitor protein (RKIP) is expressed in a number of normal human tissues and previous studies have demonstrated the prognostic value of the loss of RKIP expression in several gastrointestinal tumors. Therefore, the present study aimed to evaluate the clinical implications of RKIP expression in a series of neoplastic lesions of the anal canal. The resected tumors of 48 patients [8 high-grade intraepithelial lesions (HSILs), 14 adenocarcinomas and 26 squamous cell carcinomas (SCCs)] were immunohistochemically evaluated for RKIP expression, and the results were correlated with clinicopathological data. The results identified a decreased 5-year overall survival rate in patients with adenocarcinoma (40.8%) compared with patients with SCC (76.7%), and a decreased 5-year disease-free survival rate in patients at clinical stages III/IV (37.3 vs. 62.5 and 82.6% for clinical stages 0 and I/II, respectively). Low RKIP expression was revealed in 62.5% of HSILs, 88.5% of SCCs and 100.0% of the adenocarcinomas. High RKIP expression was associated with patient ethnicity (37.5% in non-Caucasians vs. 7.5% in Caucasians) and patient age (33.3% in younger patients vs. 0.0% in older patients). Finally, high RKIP expression was correlated with HPV16 infection status (40% in HPV- vs. 5.3% in HPV+ patients). A correlation was identified between high RKIP expression and lesions with a generally improved prognosis, such as those diagnosed in younger patients, in situ lesions and lesions of lower clinical grades; there was also a negative correlation between high RKIP expression and HPV16 positivity in patients.