RESUMO
PURPOSE: Pancreatic Ductal Adenocarcinoma (PDAC) is the most common type of pancreatic malignancies. It is known for its aggressive nature and high mortality rate. This calls for an urgent need of new prognostic and therapeutic markers that can be targeted for personalized treatment of the patient. METHODS: Among 142 patients diagnosed with pancreatic cancers at Aga Khan University Hospital, a total of 62 patients were selected based on their confirmed diagnosis of PDAC. Immunohistochemistry was performed on Formalin-Fixed Paraffin-Embedded (FFPE) sections using selected antibodies (CD44, CD133, L1CAM, HER2, PD-L1, EGFR, COX2 and cyclin D1). All the slides were scored independently by two pathologists as per the set criteria. RESULTS: Expression of all cancer stem cell markers was found to be significantly associated with one or more potential therapeutic markers. CD44 expression was significantly associated with HER2 (p = 0.032), COX2 (p = 0.005) and EGFR expression (p = 0.008). CD133 expression also showed significant association with HER2 (p = 0.036), COX2 (p = 0.004) and EGFR expression (p = 0.018). L1CAM expression was found to be associated with expression of COX2 (p = 0.017). None of the proteins markers showed association with overall survival of the patient. On the other hand, among the clinicopathological characteristics, histological differentiation (p = 0.047), lymphovascular invasion (p = 0.021) and perineural invasion (p = 0.014) were found to be significantly associated with patient's overall survival. CONCLUSION: Internationally, this is the first report that assesses the selected panel of cancer stem cell markers and potential therapeutic targets in a single study and evaluates its combined expression. The study clearly demonstrates association between expression of cancer stem cell markers and therapeutic targets hence paves a way for precision medicine for pancreatic cancer patients.
Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Células-Tronco Neoplásicas , Neoplasias Pancreáticas , Células-Tronco Neoplásicas/química , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/terapia , Imunoquímica , Biomarcadores Tumorais/análise , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Pancreatic adenocarcinoma is one of the most aggressive malignancies with extremely low survival rate. Studies have shown that the exploration of key genes can provide a basis for targeted treatment of these patients. The genomic architecture of the Pakistani pancreatic adenocarcinoma patients remains unexplored. Keeping the scenario in place, the current study aims to analyse 88 cancer related genes in Pakistani pancreatic adenocarcinoma patients in order to elucidate candidate gene(s) for targeted molecular therapy. METHODS AND RESULTS: A total 18 patients were included in the study initially and FFPE tumor samples were obtained. After confirmation of diagnosis and appropriate tumor content, DNA was extracted. Based on the quality and quantity of the extracted DNA, six pancreatic adenocarcinoma tumor samples were selected. Following to this, all the samples were subjected to targeted sequencing (Axen Cancer Panel 1). Variant detection was done and clinical significance of identified variants was assessed using ClinVar database. Targeted sequencing of tumor samples revealed a total of 29 alterations in the coding region of various genes. Among these five pathogenic variants were found in KRAS, BRCA1, TP53 and APC genes. CONCLUSION: This is the first study that explores genes involved in pancreatic adenocarcinoma from the Pakistani population. Results obtained from the pilot study can guide us about the key genetic players in the Pakistani pancreatic adenocarcinoma population. This can lead to our better understanding of the molecular targeted therapies for these patients and designing future researches on larger sample size.
Assuntos
Adenocarcinoma/genética , Adenoma/epidemiologia , Adenoma/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Adenocarcinoma/epidemiologia , Proteína da Polipose Adenomatosa do Colo/genética , Idoso , Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Feminino , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Projetos Piloto , Proteínas Proto-Oncogênicas p21(ras)/genética , Transcriptoma/genética , Proteína Supressora de Tumor p53/genética , Neoplasias PancreáticasRESUMO
PURPOSE: Deletion of Glutathione S-Transferase Theta 1 (GSTT1) encoding gene is implicated in breast cancer susceptibility, clinical outcomes, and survival. Contradictory results have been reported in different studies. The present investigation based on a representative Pakistani population evaluated the GSTT1-absent genotype in breast cancer risk and prognosis. METHODS: A prospective study comprising case-control analysis and case series analysis components was designed. Peripheral blood samples were collected from enrolled participants. After DNA extraction, GSTT1 genotyping was carried out by a multiplex PCR with ß-globin as an amplification control. Association evaluation of GSTT1 genotypes with breast cancer risk, specific tumor characteristics, and survival were the primary endpoints. RESULTS: A total of 264 participants were enrolled in the molecular investigation (3 institutions). The study included 121 primary breast cancer patients as cases and 143 age-matched female subjects, with no history of any cancer, as controls. A significant genetic association between GSTT1-absent genotype and breast cancer susceptibility (p-value: 0.03; OR: 2.13; 95% CI: 1.08-4.29) was reported. The case-series analysis showed lack of association of GSTT1 genotypes with menopause (p-value: 0.86), tumor stage (p-value: 0.12), grade (p-value: 0.32), and size (p-value: 0.07). The survival analysis revealed that GSTT1-absent genotype cases had a statistically significant shorter overall survival (OS) than those with the GSTT1-present genotype cases (mean OS: 23 months vs 33 months). The HR (95% CI) for OS in patients carrying GSTT1-absent genotype was 8.13 (2.91-22.96) when compared with the GSTT1-present genotype. CONCLUSIONS: The present study is the first report of an independent significant genetic association between GSTT1-absent genotype and breast cancer susceptibility in a Pakistani population. It is also the foremost report of the association of this genotype with OS in breast cancer cases. Upon further validation, GSTT1 variation may serve as a marker for devising better population-specific strategies. The information may have translational implications in the screening and treatment of breast cancers.