RESUMO
Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology.To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes.In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree.From the analysis of the pedigree, we were able to identify a "protective" haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model.
Assuntos
Albinismo/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Melanoma/genética , Mutação , Neoplasias Primárias Múltiplas/genética , Albinismo/diagnóstico , Biomarcadores , Biologia Computacional/métodos , Metilação de DNA , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/genética , Análise Mutacional de DNA , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/genética , Família , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Modelos Moleculares , Anotação de Sequência Molecular , Neoplasias Primárias Múltiplas/diagnóstico , Linhagem , Filogenia , Conformação Proteica , Irmãos , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genéticaRESUMO
TLRs are main actors of the innate immune response against HPV. There are very few studies on the role of TLRs mediated HPV clearance in Head and Neck oncology. Our aim was to evaluate whether TLR4 expression identifies HPV infection and/or HR-HPV integration status in oral and oropharyngeal cancers. By immunohistochemistry we assessed TLR4 levels in OSCC/OPSCC. To detect viral integration or episomic status In situ hybridization for HPV-DNA and Pyro-sequencing techniques have been performed. The relationship between TLR4 expression with HPV infection status has been investigated. ISH HPV positive samples have reported lower levels of TLR4 intensity than negative samples (p = .002). There was no statistical correlation between TLR4 intensity and PCR HPV results (p more than 0.0.5). Point-biserial correlation coefficient revealed significant association between TLR4 expression and HR-HPV integration status (p = .0001) and between TLR4 expression index and HR-HPV infection (p = .001). These data have shown that TLR4 down-regulation is strongly associated to both HPV-16 infection and its integration into the host DNA.
Assuntos
Alphapapillomavirus/fisiologia , Carcinoma de Células Escamosas/virologia , Regulação para Baixo , Neoplasias de Cabeça e Pescoço/virologia , Receptor 4 Toll-Like/metabolismo , Integração Viral , Adulto , Idoso , Idoso de 80 Anos ou mais , Alphapapillomavirus/genética , DNA Viral/isolamento & purificação , Feminino , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND AND AIMS: Lung cancer has recently been associated with human papilloma virus (HPV) infection. The most important event associated with HPV infection in cancer foresees HPV DNA integration into the host genome. Sites of integration such as the fragile site FRA3B adjacent to the FHIT frequently undergo microsatellite alterations (MAs). In this study we aim to verify the role of MAs at 3p in non-small cell lung cancer (NSCLC) with HPV positivity and eventual correlation with sex, histotype, TNM stage and cigarette smoking. METHODS: We enrolled 26 NSCLC patients previously investigated for the presence of HPV in their airways (11 HPV+ and 15 HPV-). All subjects had allelotyping analysis of DNA from exhaled breath condensate (EBC), blood and bronchial brushing of microsatellite D3S1300 located in the chromosomal region 3p. RESULTS: For the first time we described the presence of MAs at 3p in EBC of NSCLC patients with HPV positivity. MAs in EBC corresponded to those in paired brushing. The number of patients with 3p MAs was higher in the group of NSCLC with HPV positivity than with HPV negativity. No relationship between the presence and type of MAs in EBC-brushing/DNA and sex, histotype or tumor stage was found. CONCLUSION: Our results suggested that MAs at 3p are present in caucasic NSLC HPV+ patients and might be involved in lung carcinogenesis. In consideration of the possible clinical usefulness of the analysis of MAS at 3p in the EBC of HPV+ patients in the non-invasive screening for lung cancer, these results merit further studies.
