Papers by Maria Tornesello
Journal of translational medicine, 2014
Mutations in the tumor suppressor gene TP53 and proto-oncogene PIK3CA and alterations of p53 and ... more Mutations in the tumor suppressor gene TP53 and proto-oncogene PIK3CA and alterations of p53 and PIK3CA AKT mTOR pathways are common events in several human cancers. We focused on the analysis of TP53 and PIK3CA gene variations in adenocarcinoma, squamous cell carcinoma as well as in intraepithelial neoplasia grade 3 of the cervix. DNA samples from 28 cervical adenocarcinoma, 55 squamous cell carcinoma and 31 intraepithelial neoplasia grade 3 (CIN3), previously characterized in terms of human papillomavirus (HPV) prevalence and genotype distribution, were analyzed for TP53 and PIK3CA mutations in the exons 4-9 and exon 9, respectively. Single nucleotide substitutions in TP53 and PIK3CA genes were detected in 36% and 11% of adenocarcinoma, in 16% and in 5% of squamous cell carcinoma, and in 13% and none of CIN 3, respectively. Nucleotide changes in TP53 were significantly more frequent in adenocarcinoma cases than in squamous cell carcinoma and CIN3 (P = 0.035) and were independent f...
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International journal of cancer. Journal international du cancer, 2008
The causative role of human papillomaviruses (HPV) and HPV16 variants has been extensively studie... more The causative role of human papillomaviruses (HPV) and HPV16 variants has been extensively studied in uterine cervix dysplastic lesions and invasive carcinoma; few such studies, however, have been performed in penile tumors. We have investigated HPV genotype and HPV16 variant distribution on 41 penile cancer biopsies from Italian patients. Cases were extracted from the respective pathology departments databases of National Cancer Institutes in Naples and Milan. HPV sequences were detected by PCR and characterized by direct sequence analysis. Among the 19 HPV-positive cases (46.3%) 2 viral genotypes were identified (HPV16 and 18) with HPV16 accounting for 94.7% (18 out of 19) of the infections. Sequence analysis of E6, E7 genes and long control region (LCR) of 18 HPV16 isolates allowed the identification of European (E-G-350) and non-European (AA and Af-1) variants in 44.4% and in 55.6% of the samples, respectively. The AA variant alone represented 44.4% of all HPV16 infections, a si...
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Journal of medical virology, 2006
The aim of the present investigation was to define the spectrum of mucosotropic human papillomavi... more The aim of the present investigation was to define the spectrum of mucosotropic human papillomaviruses among 414 Italian women with normal cervices (n = 183), low- and high-grade cervical squamous intraepithelial lesions (n = 101 and 65, respectively), and invasive squamous cervical carcinomas (n = 65). Human papillomaviruses were detected by broad spectrum consensus-primer-pairs MY09/MY11 and GP5+/GP6+-based polymerase chain reaction using three amplification methods and were characterized by nucleotide sequence analysis. The prevalence rates of HPV infections was 19.7%, 63.4%, 80%, and 81.5% in patients with normal cervices, low-grade, and high-grade squamous intraepithelial lesions, and cervical carcinomas, respectively. Among the 205 HPV-positive patients, a total of 31 mucosal HPV genotypes were identified of which 16 types, epidemiological classified as high-risk viruses (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 66, 68, 73, and 82), have been found in 16.9%, 50.1%, 6...
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The Journal of general virology, 1997
Sequence variations in the E6/E7 (nt 34-880) and the L1-(nt 6584-7035) ORFs, and in the long cont... more Sequence variations in the E6/E7 (nt 34-880) and the L1-(nt 6584-7035) ORFs, and in the long control region (LCR) (nt 7289-93) of human papillomavirus type 16 (HPV-16) were analysed in five penile carcinoma biopsies obtained from Ugandan patients. Uganda is a country with a high incidence of genital cancers. All five isolates were classified as members of African-1 lineage (Af1) by phylogenetic analysis based on LCR sequences. The E6 gene phylogenetic analysis, however, showed that four isolates fell into a new subclass designated Af1-u. This subclass, characterized by three point mutations located at the 5' end of the E6 gene with resulting changes in amino acids at positions 10 and 14, is distinguishable from the Af1 class by the absence of synonymous mutations at nt 286 and 289. The nonsynonymous substitution at nt 335 was present in three out of five samples. The E6 Af1 mutation pattern was present in only a single Ugandan HPV-16 isolate. Nucleotide sequence analysis of the ...
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Intervirology, 1993
To investigate the possible direct/indirect role of Human immunodeficiency virus (HIV) as a cofac... more To investigate the possible direct/indirect role of Human immunodeficiency virus (HIV) as a cofactor in human papillomavirus (HPV) oncogenesis, cotransfection experiments were carried out in which a recombinant plasmid containing the HPV16 long control region (LCR) linked to the chloramphenicol acetyltransferase (CAT) gene was cotransfected into cultured cells with a plasmid expressing HIV-1 Tat protein. Tat expression efficiency and transactivation activity were evaluated in different cell lines by cotransfecting plasmids containing the HIV tat gene and HIV LTR-driven CAT-coding sequences. HeLa and CaSki cell lines represented the most appropriate recipient cells for Tat-directed transactivation of both the HIV LTR and the HPV LCR promoters. Furthermore, HIV tat was transfected into HeLa cells (containing 10-20 copies per cell of HPV18), and HPV18 E7 protein expression was evaluated by a radioimmunoprecipitation assay using polyclonal antibodies against the E7 protein. Our results ...
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PLOS ONE, 2015
The variability in the association of host innate immune response to Hepatitis C virus (HCV) infe... more The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression. We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher's exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC. Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases.
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BioMed Research International, 2013
Cervical cancer arises from cells localized in the ectoendocervical squamocolumnar junction of th... more Cervical cancer arises from cells localized in the ectoendocervical squamocolumnar junction of the cervix persistently infected with one of about 13 human papillomavirus (HPV) genotypes. The majority of HPV infections induces low grade squamous epithelial lesions that in more than 90% of cases spontaneously regress and in about 10% eventually progress to high grade lesions and even less frequently evolve to invasive cancer. Tumor progression is characterized by (1) increased expression of E6 and E7 genes of high risk HPVs, known to bind to and inactivate p53 and pRb oncosuppressors, respectively; (2) integration of viral DNA into host genome, with disruption of E2 viral genes and host chromosomal loci; and (3) molecular alterations of key regulators of cell cycle. Molecular markers with high sensitivity and specificity in differentiating viral infections associated with cellular abnormalities with high risk of progression are strongly needed for cervical cancer screening and triage. This review will focus on the analysis of clinical validated or candidate biomarkers, such as HPV DNA, HPV E6/E7 mRNA, HPV proteins, p16(INK4a) and Ki67, TOP2A and MCM2 cellular factors, and DNA methylation profiles, which will likely improve the identification of premalignant lesions that have a high risk to evolve into invasive cervical cancer.
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SciVee, 2000
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Journal of Translational Medicine, 2005
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Infectious Agents and Cancer, 2007
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Virology, 2010
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Virus Research, 2012
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Cancer Letters, 2014
Head and neck cancers are a heterogeneous group of malignancies accounting for approximately 600,... more Head and neck cancers are a heterogeneous group of malignancies accounting for approximately 600,000 new cases every year worldwide. Human papillomavirus (HPV)-related oropharyngeal cancers represent a new nosological entity for pathogenesis, molecular mechanisms, prognostic trend and therapeutic response. Several clinical trials have shown that HPV-positive/p16-positive cancer patients have a favorable prognosis demanding for de-escalation of current therapies. Comprehensive genomic analyses allowed to identify specific genetic alterations in targetable genes envisaging novel approaches to treat different subset of HPV-related and HPV-unrelated oropharyngeal cancers. Furthermore virus associated head and neck cancers may benefit from new developed immunotherapies targeting HPV E6 and E7 oncoproteins. We reviewed recent studies on the role of HPV infection in these cancers and present our current understanding of carcinogenic mechanisms providing possible novel approaches to cancer treatment.
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Journal of Translational Medicine, 2015
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Frontiers in Oncology, 2014
Human papillomavirus (HPV) infection is highly prevalent in women migrating from countries where ... more Human papillomavirus (HPV) infection is highly prevalent in women migrating from countries where cervical screening is not implemented. The variety of HPV genotypes, their prevalence and the association with cervical abnormalities has been investigated by several groups in women moving mainly from Eastern Europe, Africa, and Southern Asia to Italy. All studies are concordant on the elevated rate of HPV infection among immigrants, which is four times higher than that observed among age-matched Italian women. The HPV prevalence among short-term migrants and characterization of viral variants showed that the high prevalence of HPV reflects either individual lifestyle or high prevalence of HPV in the country of origin. The high burden of HPV infection correlates very well with the high incidence of cervical cancer in migrant women. In fact, during the years 2000-2004 the cervical cancer incidence in women from Central and Eastern Europe and living in Central Italy was 38.3 per 100,000, which is statistically significant higher than that of native Italian women (6 per 100,000). In this study, we pooled together the results of three independent studies originally designed to assess the distribution and the prevalence of HPV genotypes among 499 immigrant women living in Southern Italy. A total of 39 mucosal HPV genotypes were identified. The 12 genotypes (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) classified as carcinogenic to humans (group 1) accounted for >80% of all infections. HPV16 was the most common viral type in all groups with frequency rates ranging from 15.4% in Africa to 51.1% in Eastern and Southern European HPV-positive women. The high prevalence of oncogenic HPVs and cervical cancer risk among migrant women, together with the lower participation in screening programs, demands for an urgent implementation of preventive strategies to increase screening and vaccine coverage and viral monitoring of uncommon HPV genotypes potential spreading in settled population.
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Transgenic Research, 2008
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Retrovirology, 2007
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Oncology, 2009
Several studies have examined the association of codon 72 polymorphism of the TP53 gene, encoding... more Several studies have examined the association of codon 72 polymorphism of the TP53 gene, encoding either arginine or proline, in several tumor types but none have investigated its role in Kaposi's sarcoma (KS) development. In this prevalent case-control study, 67 cutaneous lesions of classic, iatrogenic, endemic as well as epidemic KS from African (n = 22) and Caucasian (n = 45) patients, and blood samples from 150 healthy controls (n = 57 African, n = 93 Caucasian) have been analyzed for arginine and proline allele distribution. Among African cases the proline homozygous, heterozygous and arginine homozygous genotype frequencies were 50.0, 31.8 and 18.2%, respectively, and among controls 54.4, 40.3, and 5.3%, respectively (p = 0.1872). Conversely, among Caucasian cases genotype distributions were 6.7, 55.6, and 37.8%, and among controls 7.5, 34.4, and 58.1%, respectively (p = 0.0567). No significant differences in arginine and proline allele distribution were observed when the cases were stratified by HIV status/tumor type. The results obtained in this study suggest that p53 polymorphism at codon 72 does not represent a risk factor for the development of all forms of KS, either among African or among Caucasian populations.
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Journal of Virology, 2005
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Journal of Virological Methods, 2005
The geographical distribution of human immunodeficiency virus type 1 (HIV-1) subtypes show, with ... more The geographical distribution of human immunodeficiency virus type 1 (HIV-1) subtypes show, with the exception of some African Countries, a specific pattern. However, the significant phenomenon of migration to Western Countries, coupled to inter-ethnic blending, may result in a constant introduction and spread of novel subtypes and/or recombinant forms in previously homogeneous HIV-1 epidemics. The need to identify and trace these events prompted the development of a rapid and specific bio-molecular tool for the HIV-1 screening, based on the well-established Heteroduplex Mobility Assay (HMA). This modified version of HMA (rHMA) has been designed to detect, by a short electrophoretic analysis, HIV-1 isolates remarkably divergent form the local predominant clade, for subsequent more accurate genetic and phylogenetic analyses. The method has been validated for both C2-V5 region of env gene and the p24-p7 region of the gag gene, by proof-of-concept experiments performed on a panel of reference standards representing the globally most prevalent HIV-1 subtypes, and applied to screen Italian and Ugandan field isolates. The rHMA experimental conditions identified in this study have been shown to be specific and reliable for both sub-genomic regions of each subtype used. In the context of nationwide monitoring programs, the rHMA may represent a powerful tool for the HIV-1 molecular surveillance in both developed and developing countries, particularly those characterized by mono/dual-clade HIV-1 epidemic, which is relevant for epidemiological studies and for the development of preventive and therapeutic strategies.
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Papers by Maria Tornesello