RESUMEN
Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.
Asunto(s)
Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/inmunología , Neoplasias Nasofaríngeas/inmunología , Escape del Tumor/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/inmunología , Línea Celular Tumoral , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/terapia , Infecciones por Virus de Epstein-Barr/virología , Femenino , Regulación Viral de la Expresión Génica/inmunología , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/patogenicidad , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Metionina Adenosiltransferasa/antagonistas & inhibidores , Metionina Adenosiltransferasa/metabolismo , Ratones , FN-kappa B/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virología , Nasofaringe/inmunología , Nasofaringe/patología , Nasofaringe/cirugía , Nasofaringe/virología , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Eliminación de Secuencia , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Escape del Tumor/efectos de los fármacos , Secuenciación Completa del Genoma , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The transforming growth factor-ß (TGF-ß) signalling pathway plays a critical role in carcinogenesis. It has a biphasic action by initially suppressing tumorigenesis but promoting tumour progression in the later stages of disease. Consequently, the functional outcome of TGF-ß signalling is strongly context-dependent and is influenced by various factors including cell, tissue and cancer type. Disruption of this pathway can be caused by various means, including genetic and environmental factors. A number of human viruses have been shown to modulate TGF-ß signalling during tumorigenesis. In this review, we describe how this pathway is perturbed in Epstein-Barr virus (EBV)-associated cancers and how EBV interferes with TGF-ß signal transduction. The role of TGF-ß in regulating the EBV life cycle in tumour cells is also discussed.
RESUMEN
Genome-wide association studies have discovered multiple single nucleotide polymorphisms (SNPs) associated with the risk of common diseases. The objective of this study was to demonstrate the replication of previously published SNPs that showed statistical significance for breast cancer in the Malaysian population. In this case-control study, 80 subjects for each group were recruited from various hospitals in Malaysia. A total of 768 SNPs were genotyped and analyzed to distinguish risk and protective alleles. A total of three SNPs were found to be associated with increased risk of breast cancer while six SNPs showed protective effect. All nine were statistically significant SNPs (p ≤ 0.01), five SNPs from previous studies were successfully replicated in our study. Significant modifiable (diet) and non-modifiable (family history of breast cancer in first degree relative) risk factors were also observed. We identified nine SNPs from this study to be either conferring susceptibility or protection to breast cancer which may serve as potential markers in risk prediction.
RESUMEN
Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in NPC and identify LPA signalling as a potential therapeutic target in this disease.
Asunto(s)
Regulación hacia Abajo/fisiología , Infecciones por Virus de Epstein-Barr/fisiopatología , Regulación Neoplásica de la Expresión Génica/fisiología , Lisofosfolípidos/fisiología , Neoplasias Nasofaríngeas/fisiopatología , Receptores del Ácido Lisofosfatídico/fisiología , Transducción de Señal/fisiología , Adenocarcinoma/patología , Adenocarcinoma/fisiopatología , Carcinoma , Línea Celular Tumoral , Movimiento Celular/fisiología , Herpesvirus Humano 4/fisiología , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patología , Hidrolasas Diéster Fosfóricas/fisiología , Receptores del Ácido Lisofosfatídico/genética , Linfocitos T Citotóxicos/patología , Proteínas de la Matriz Viral/fisiologíaRESUMEN
BACKGROUND & OBJECTIVES: Colorectal cancer (CRC) is second only to breast cancer as the leading cause of cancer-related deaths in Malaysia. In the Asia-Pacific area, it is the highest emerging gastrointestinal cancer. The aim of this study was to identify single nucleotide polymorphisms (SNPs) and environmental factors associated with CRC risk in Malaysia from a panel of cancer associated SNPs. METHODS: In this case-control study, 160 Malaysian subjects were recruited, including both with CRC and controls. A total of 768 SNPs were genotyped and analyzed to distinguish risk and protective alleles. Genotyping was carried out using Illumina's BeadArray platform. Information on blood group, occupation, medical history, family history of cancer, intake of red meat and vegetables, exposure to radiation, smoking and drinking habits, etc was collected. Odds ratio (OR), 95% confidence interval (CI) were calculated. RESULTS: A panel of 23 SNPs significantly associated with colorectal cancer risk was identified (P<0.01). Of these, 12 SNPs increased the risk of CRC and 11 reduced the risk. Among the environmental risk factors investigated, high intake of red meat (more than 50% daily proportion) was found to be significantly associated with increased risk of CRC (OR=6.52, 95% CI :1.93-2.04, P=0.003). Two SNPs including rs2069521 and rs10046 in genes of cytochrome P450 (CYP) superfamily were found significantly associated with CRC risk. For gene-environment analysis, the A allele of rs2069521 showed a significant association with CRC risk when stratified by red meat intake. INTERPRETATION & CONCLUSIONS: In this preliminary study, a panel of SNPs found to be significantly associated with CRC in Malaysian population, was identified. Also, red meat consumption and lack of physical exercise were risk factors for CRC, while consumption of fruits and vegetables served as protective factor.
Asunto(s)
Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Sistema Enzimático del Citocromo P-450/genética , Estudios de Casos y Controles , Dieta , Ejercicio Físico , Femenino , Genotipo , Humanos , Malasia/epidemiología , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
There is growing global interest to stratify men into different levels of risk to developing prostate cancer, thus it is important to identify common genetic variants that confer the risk. Although many studies have identified more than a dozen common genetic variants which are highly associated with prostate cancer, none have been done in Malaysian population. To determine the association of such variants in Malaysian men with prostate cancer, we evaluated a panel of 768 SNPs found previously associated with various cancers which also included the prostate specific SNPs in a population based case control study (51 case subjects with prostate cancer and 51 control subjects) in Malaysian men of Malay, Chinese and Indian ethnicity. We identified 21 SNPs significantly associated with prostate cancer. Among these, 12 SNPs were strongly associated with increased risk of prostate cancer while remaining nine SNPs were associated with reduced risk. However, data analysis based on ethnic stratification led to only five SNPs in Malays and 3 SNPs in Chinese which remained significant. This could be due to small sample size in each ethnic group. Significant non-genetic risk factors were also identified for their association with prostate cancer. Our study is the first to investigate the involvement of multiple variants towards susceptibility for PC in Malaysian men using genotyping approach. Identified SNPs and non-genetic risk factors have a significant association with prostate cancer.
Asunto(s)
Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Etnicidad/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Malasia/epidemiología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: The identification of high-risk individuals can help to improve early cancer detection and patient survival. Risk assessment, however, can only be accomplished if the risk factors are known. To date, the genetic risk factors for ovarian cancer, other than mutations in the BRCA1/2 genes, have never been systematically explored in Malaysia. The present study aims to identify from a panel of cancer-associated single-nucleotide polymorphisms (SNPs), those associated with ovarian cancer risk in Malaysia. METHODS: A total of 768 SNPs associated with various cancers among Asians were identified through a search of the relevant literature, and these SNPs were then screened for their association with ovarian cancer. A total of 160 Malaysian subjects were recruited for the study, including both ovarian cancer patients and controls. Genotyping was carried out using Illumina BeadArray platform. RESULTS: A panel of 45 SNPs that are significantly (p<0.05) associated with ovarian cancer risk was identified. These ovarian cancer-associated SNPs were located in genes implicated in various pathways of carcinogenesis. Of these 45 SNPs, 5 have been previously associated with either ovarian cancer risk or survival. CONCLUSION: This study has identified a panel of 45 SNPs that are significantly associated with ovarian cancer in a Malaysian population.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genética , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Genes BRCA1 , Genotipo , Humanos , Malasia/epidemiología , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: Nasopharyngeal carcinoma (NPC) is endemic in Southern Chinese and Southeast Asian populations. Geographical and ethnic clustering of the cancer is due to genetic, environmental, and lifestyle risk factors. This case-control study aimed to identify or confirm both genetic and non-genetic risk factors for NPC in one of the endemic countries, Malaysia. MATERIALS AND METHOD: A panel of 768 single-nucleotide polymorphisms (SNPs) previously associated with various cancers and known non-genetic risk factors for NPC were selected and analyzed for their associations with NPC in a case-control study. RESULTS: Statistical analysis identified 40 SNPs associated with NPC risk in our population, including 5 documented previously by genome-wide association studies (GWAS) and other case-control studies; the associations of the remaining 35 SNPs with NPC were novel. In addition, consistent with previous studies, exposure to occupational hazards, overconsumption of salt-cured foods, red meat, as well as low intake of fruits and vegetables were also associated with NPC risk. CONCLUSIONS: In short, this study confirmed and/or identified genetic, environmental and dietary risk factors associated with NPC susceptibility in a Southeast Asian population.