RESUMO
Our research group demonstrated, in a precedent study, the prognostic power of the 3p microsatellites alterations (MAs) detectable in exhaled breath condensate (EBC) in NSCLC patients. The analysis of genetic markers in the EBC might have precious clinical and economic consequences when inserted in diagnostic and follow up programs for lung cancer. The aim of this study was to evaluate the prognostic value of a new panel of MAs in the EBC of patients with NSCLC. We enrolled 45 NSCLC patients during a period of 36 months and the follow-up period was 156 weeks. We analyzed MAs for eight markers in EBC samples: D3S2338, D3S1266, D3S1300, D3S1304, D3S1289, D5S2094, D3S1313, and AFMa305ye1. Our study showed that the presence of more than 2 simultaneous MAs reduces outcome in NSCLC patients. The new panel of eight microsatellites markers proposed in EBC samples could have a potential clinical role in assessing survival in lung cancer patients.
RESUMO
BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Serina-Treonina Quinases TOR/genética , Idoso , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Intervalo Livre de Doença , Cloridrato de Erlotinib/farmacologia , Feminino , Gefitinibe , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Resultado do TratamentoRESUMO
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.
Assuntos
Alphapapillomavirus , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 3 , Neoplasias Pulmonares/genética , Instabilidade de Microssatélites , Infecções por Papillomavirus/complicações , Hidrolases Anidrido Ácido/genética , Idoso , Alphapapillomavirus/genética , Alphapapillomavirus/isolamento & purificação , Testes Respiratórios , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/virologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/virologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Infecções por Papillomavirus/virologia , Fumar/efeitos adversosRESUMO
BACKGROUND: Airways of lung cancer patients are often colonized by fungi. Some of these colonizing fungi, under particular conditions, produce cancerogenic mycotoxins. Given the recent interest in the infective origin of lung cancer, with this preliminary study we aim to give our small contribution to this field of research by analysing the fungal microbiome of the exhaled breath condensate of lung cancer patients from Puglia, a region of Italy. METHODS: We enrolled 43 lung cancer patients and 21 healthy subjects that underwent exhaled breath condensate and bronchial brushing collection. The fungal incidence and nature of sample collected were analysed by using a selected media for Aspergillus species. RESULTS: For the first time we were able to analyse the fungal microbioma of the exhaled breath condensate. 27.9% of lung cancer patients showed a presence of Aspergillus niger, or A. ochraceus or Penicillium ssp. while none of the healthy subjects did so. CONCLUSION: The results confirmed the high percentage of fungal colonization of the airways of lung cancer patients from Puglia, suggesting the need to conduct further analyses in this field in order to evaluate the exact pathogenetic role of these fungi in lung cancer as well as to propose efficient, empirical therapy.