RESUMO
The study aimed to screen mutation of human homeostatic iron regulator (HFE) in colorectal carcinoma (CRC) and detect their associations with clinicopathological parameters. Expression of HFE was determined by quantitative polymerase chain reaction in matched CRC and non neoplastic colorectal mucosal tissue of 76 patients. Genomic DNA extracted were subjected to high high-resolution melt curve analysis and Sanger sequencing to detect mutations in HFE. The associations of the identified mutations with a variety of clinical features were determined. Approximately 60% of CRC showed low HFE expression. Of the ten 10 mutations identified in exons 2 and 4, c.187C>G (H63D), c845G>A (C282Y), c.193A>T (S65C), g.3828T>C, g.5795T>C, and g.5728G>A were known mutations. Four novel mutations were discovered; : c.184G>A, c.220T>G, c.322A>C, and c.324T>C. Heterozygous H63D and C282Y mutations were seen in 71% and 49% of cancer tissue, respectively. Tumour site (p = 0.048) and gender (p = 0.039) were significantly associated with H63D and C282Y mutation status, respectively. Local spread of cancer was significantly associated with C282Y mutations in CRC cancer and adjacent non-neoplastic tissue (p = 0.029 & and p = 0.004, respectively). There was a statistically significant association between H63D and C282Y negativity in matched non-neoplastic colorectal mucosa tissue and pathological staging of cancer (p = 0.047 & and p = 0.001, respectively). Patients with H63D and C282Y mutations in cancer tissue tend to have higher survival rates. Hence HFE mutations are common in CRC and are associated with clinicopathological parameters, implying the potential clinical significance of HFE mutations in colorectal carcinogenesis.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteína da Hemocromatose/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
PURPOSE: Heme is a crucial compound for cell survival but is also equipped with the potential to be toxic and carcinogenic to cells. However, with the recent advancement of knowledge regarding ferroptosis, the iron mediated cell death, heme can be postulated to induce tumour suppression through ferroptosis. This review summarizes the literature on the carcinogenic and anticarcinogenic properties of heme with specific emphasis on the alterations observed on heme synthesis, metabolism and transport in tumour cells. METHODS: Literature search was performed in PubMed data base using the MeSH terms 'heme iron or heme', 'cancer or carcinogenesis' and 'tumour suppression' or 'anticarcinogenic properties. Out of 189 results, 166 were relevant to the current review. RESULTS: Heme supports carcinogenesis via modulation of immune cell function, promoting inflammation and gut dysbiosis, impeding tumour suppressive potential of P53 gene, promoting cellular cytotoxicity and reactive oxygen species generation and modulating Nfr2 /HO-1 axis. The carcinogenic and anticarcinogenic properties of heme are both dose and oxygen concentration dependant. At low doses, heme is harmless and even helpful in maintaining the much-needed redox balance within the cell. However, when heme exceeds physiological concentrations, it could initiate and propagate carcinogenesis, due to its ability to produce reactive oxygen species (ROS). The same phenomenon of heme mediated ROS generation could be manipulated to initiate tumour suppression via ferroptosis, but the therapeutic doses are yet to be determined. CONCLUSION: Heme iron possesses powerful carcinogenic and anticarcinogenic properties which are dosage and oxygen availability dependant.
Assuntos
Carcinogênese/patologia , Heme/metabolismo , Ferro/metabolismo , Neoplasias/patologia , Neoplasias/prevenção & controle , Carcinogênese/genética , Carcinogênese/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Somatic copy-number alterations are commonly found in cancer and play key roles in activating oncogenes and deactivating tumor suppressor genes. Digital polymerase chain reaction is an effective way to detect the changes in copy number. In esophageal adenocarcinoma, detection of somatic copy-number alterations could predict the prognosis of patients as well as the response to therapy. This chapter will review the methods involved in digital polymerase chain reaction for the research or potential clinical applications in esophageal adenocarcinoma.
Assuntos
Adenocarcinoma/genética , Variações do Número de Cópias de DNA , DNA/análise , Neoplasias Esofágicas/genética , Reação em Cadeia da Polimerase/métodos , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Esôfago/patologia , Humanos , Reação em Cadeia da Polimerase/instrumentação , Prognóstico , Software , Resultado do TratamentoRESUMO
Esophageal adenocarcinoma is heterogeneous and studies have reviewed many important mutations that contribute to the pathogenesis of the cancer. These discoveries have helped paved the way into identifying new gene markers or gene targets to develop novel molecular directed therapy for better patient outcomes in esophageal adenocarcinoma. Despite the recent bloom in next-generation sequencing, Sanger sequencing still represents the gold standard method for the study of the driver genes in esophageal adenocarcinoma. This chapter focuses on the sequencing techniques in identification of single gene mutations.
