RESUMO
BACKGROUND: Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC). OBJECTIVE: We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals. METHODS: A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology. RESULTS: We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics. CONCLUSION: This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.
Assuntos
Alphapapillomavirus , Carcinoma de Células Escamosas , Acalasia Esofágica , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Infecções por Papillomavirus , Brasil , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiologia , DNA Viral/genética , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/epidemiologia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/epidemiologia , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Estudos RetrospectivosRESUMO
Esophageal cancer is an aggressive tumor that has a high rate of incidence and mortality worldwide. It is the 10th most frequent type in Brazil, being squamous cell carcinoma (ESCC) the predominant subtype. There is currently an incessant search to identify the frequently altered genes associated with esophageal squamous cell carcinoma biology that could be druggable. This study aimed to analyze the somatic mutation profile of a large panel of cancer-related genes in Brazilian ESCC. In a series of 46 ESCC diagnoses at Barretos Cancer Hospital, DNA isolated from paired fresh-frozen and blood tissue, a panel of 150 cancer-related genes was analyzed by next-generation sequencing. The genes with the highest frequency of mutations were TP53 (39/46, 84.8%), followed by NOTCH1 (7/46, 15.2%), NFE2L2 (5/46, 10.8%), RB1 (3/46, 6.5%), PTEN (3/46, 6.5%), CDKN2A (3/46, 6.5%), PTCH1 (2/46, 4.3%) and PIK3CA (2/46, 4.3%). There was no significant association between molecular and patients' clinicopathological features. Applying an evolutionary action score of p53 (EAp53), we observed that 14 (35.9%) TP53 mutations were classified as high-risk, yet no association with overall survival was observed. Concluding, this the largest mutation profile of Brazilian ESCC patients, which helps in the elucidation of the major cancer-related genes in this population.
Assuntos
Carcinoma de Células Escamosas do Esôfago/epidemiologia , Carcinoma de Células Escamosas do Esôfago/genética , Transcriptoma/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Brasil/epidemiologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Feminino , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genéticaRESUMO
Cervical cancer is the fourth most common cancer in women. Although cure rates are high for early stage disease, clinical outcomes for advanced, metastatic, or recurrent disease remain poor. To change this panorama, a deeper understanding of cervical cancer biology and novel study models are needed. Immortalized human cancer cell lines such as HeLa constitute crucial scientific tools, but there are few other cervical cancer cell lines available, limiting our understanding of a disease known for its molecular heterogeneity. This study aimed to establish novel cervical cancer cell lines derived from Brazilian patients. We successfully established one (HCB-514) out of 35 cervical tumors biopsied. We confirmed the phenotype of HCB-514 by verifying its' epithelial and tumor origin through cytokeratins, EpCAM and p16 staining. It was also HPV-16 positive. Whole-exome sequencing (WES) showed relevant somatic mutations in several genes including BRCA2, TGFBR1 and IRX2. A copy number variation (CNV) analysis by nanostring and WES revealed amplification of genes mainly related to kinases proteins involved in proliferation, migration and cell differentiation, such as EGFR, PIK3CA, and MAPK7. Overexpression of EGFR was confirmed by phospho RTK-array and validated by western blot analysis. Furthermore, the HCB-514 cell line was sensitive to cisplatin. In summary, this novel Brazilian cervical cancer cell line exhibits relevant key molecular features and constitutes a new biological model for pre-clinical studies.
Assuntos
Papillomavirus Humano 16 , Proteínas de Neoplasias , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Sequenciamento do ExomaRESUMO
A supposed role for persistent high-risk human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC) etiology has been suggested by a number of studies. Concomitantly, megaesophagus induced by the Trypanosoma cruzi cell-cycle activity also shows a potential association with ESCC. This review discusses esophageal cancer and the potential association between chagasic megaesophagus and HPV as risk factors for ESCC development.