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Nucleotide variants and protein expression of TP53 in a Sri Lankan cohort of patients with head and neck cancer.

ABSTRACT: Head and neck cancer (HNC) is the leading cancer in Sri Lankan males and second most common cancer among Sri Lankan females. This is the first study, to the best of our knowledge, that has focused on investigating the association between TP53 somatic DNA variants, with p53 protein expression and risk factors in a cohort of Sri Lankan patients with HNC. A total of 44 patients with cancer and 20 healthy controls were studied. In total, 36 genomic DNA sequence variants were found, including several novel variants (two deletions in exons 4 and 6, two in the 3' untranslated region and several intronic variants). A total of 14 tumour samples carried pathogenic TP53 mutations. A random selection of 24 samples was analysed immunohistochemically for p53 protein expression. All the samples with point missense variants were strongly immuno?positive, whereas, samples with nonsense and frameshift TP53 variants were immuno?negative for p53 immunohistochemical staining. Although, the human papilloma virus is a known risk factor for HNC, results from the present study identified an absence or lower level of infection in the Sri Lankan cohort.

SUBMITTER: Manoharan V

PROVIDER: S-EPMC6423636 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Nucleotide variants and protein expression of TP53 in a Sri Lankan cohort of patients with head and neck cancer.

Manoharan Vahinipriya V Karunanayake Eric Hamilton EH Tennekoon Kamani Hemamala KH De Silva Sumadee S De Silva Kanishka K Angunawela Preethika P Lunec John J

Molecular medicine reports 20190211 4

Head and neck cancer (HNC) is the leading cancer in Sri Lankan males and second most common cancer among Sri Lankan females. This is the first study, to the best of our knowledge, that has focused on investigating the association between TP53 somatic DNA variants, with p53 protein expression and risk factors in a cohort of Sri Lankan patients with HNC. A total of 44 patients with cancer and 20 healthy controls were studied. In total, 36 genomic DNA sequence variants were found, including several ...[more]

PMID: 30816478

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Project description:BackgroundMelioidosis is a life threatening infectious disease caused by the gram-negative bacillus Burkholderia pseudomallei predominantly found in southeast Asia and northern Australia. Studying the host transcription profiles in response to infection is crucial for understanding disease pathogenesis and correlates of disease severity, which may help improve therapeutic intervention and survival. The aim of this study was to analyze gene expression levels of human host factors in melioidosis patients and establish useful correlation with disease biomarkers, compared to healthy individuals and patients with sepsis caused by other pathogens.MethodsThe study population consisted of 30 melioidosis cases, 10 healthy controls and 10 sepsis cases caused by other pathogens. Total RNA was extracted from peripheral blood mononuclear cells (PBMC's) of study subjects. Gene expression profiles of 25 gene targets including 19 immune response genes and 6 epigenetic factors were analyzed by real time quantitative polymerase chain reaction (RT-qPCR).Principal findingsInflammatory response genes; TLR4, late onset inflammatory mediator HMGB1, genes associated with antigen presentation; MICB, PSMB2, PSMB8, PSME2, epigenetic regulators; DNMT3B, HDAC1, HDAC2 were significantly down regulated, whereas the anti-inflammatory gene; IL4 was up regulated in melioidosis patients compared to sepsis cases caused by other pathogens. Septicaemic melioidosis cases showed significant down regulation of IL8 compared to sepsis cases caused by other pathogens. HMGB1, MICB, PSMB8, PSMB2, PSME2, HDAC1, HDAC2 and DNMT3B showed consistent down regulation of gene expression in melioidosis patients compared to other sepsis infection, irrespective of comorbidities such as diabetes, duration of clinical symptoms and antibiotic treatment.SignificanceSpecific immune response genes and epigenetic regulators are differentially expressed among melioidosis patients and patients with sepsis caused by other pathogens. Therefore, these genes may serve as biomarkers for disease diagnosis to distinguish melioidosis from cases of sepsis due to other infections and therapeutic intervention for melioidosis.

Project description:BackgroundGlucose-6-phosphate dehydrogenase (G6PD) is an enzyme that plays an important role in many cellular functions. Deficiency of this enzyme results from point mutations in the coding region of the G6PD gene. G6PD-deficiency is important in malaria, as certain anti-malarial drugs could induce haemolysis in such patients and mutations in this gene may influence the susceptibility or resistance to the disease. Detailed information on genetic variations in the G6PD gene for Sri Lankan populations is yet to be revealed. This study describes a set of G6PD mutations present in a Sri Lankan population and their association with uncomplicated malaria.MethodsDNA was extracted from 1,051 individuals. Sixty-eight SNPs in the region of the G6PD gene were genotyped. A database created during the 1992-1993 malaria epidemic for the same individuals was used to assess the associations between the G6PD SNPs and parasite density or disease severity of uncomplicated malaria infections. Linkage disequilibrium for SNPs and haplotype structures were identified.ResultsSeventeen genetic variants were polymorphic in this population. The mutant allele was the major allele in 9 SNPs. Common G6PD variants already described in Asians or South-Asians seemed to be absent or rare in this population. Both the severity of disease in uncomplicated malaria infections and parasitaemia were significantly lower in males infected with Plasmodium falciparum carrying the ancestral allele of rs915942 compared to those carrying the mutant allele. The parasite density of males infected with P. falciparum was significantly lower also in those who possessed the mutant alleles of rs5986877, rs7879049 and rs7053878. Two haplotype blocks were identified, where the recombination rates were higher in males with no history of malaria when compared to those who have experienced the disease in the past.ConclusionsThis is the most detailed survey of G6PD SNPs in a Sri Lankan population undertaken so far that enabled novel description of single nucleotide polymorphisms within the G6PD gene. A few of these genetic variations identified, demonstrated a tendency to be associated with either disease severity or parasite density in uncomplicated disease in males. Known G6PD gene polymorphisms already described from elsewhere were either absent or rare in the local study population.

Project description:PurposeSeveral single nucleotide polymorphisms (SNPs) have been reported to be associated with clinicopathological profiles in sporadic breast cancer based on studies conducted on major population groups. The knowledge of the effects of these common genetic variants in South Asian populations remains limited. The present study aimed to investigate the association between a selected set of SNPs and the clinicopathological profiles in sporadic breast cancer in Sri Lankan women.MethodsA total of 350 postmenopausal women with histologically confirmed invasive breast cancer were genotyped for 58 SNPs located in 36 breast cancer related genes. The clinicopathological factors that were investigated included age of onset, tumor histologic grade, and lymph node involvement, as well as estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) status. Association testing was performed using logistic regression models adjusted for confounding factors.ResultsSeven SNPs showed significant associations with clinicopathological profiles in breast cancer. The G allele of BRCA1:rs799917 (p=0.047; β [standard error; SE]=-1.069 [0.537]) and the G allele of NQO2:rs17136117 (p=0.040, β [SE]=1.901 [0.923]) were found to be associated with age of onset between 50 and 59 years. The C allele of CDH1:rs13689 (odds ratio [OR], 2.121; p=0.033) was found to be associated with ER-positive breast cancer. The A allele of AKT1:rs1130214 (OR, 2.095; p=0.011) and the C allele of NQO2:rs2071002 (OR, 1.632; p=0.045) were associated with HER2-positive breast cancer. The C allele of BRCA2:rs15869 (OR, 1.600; p=0.041) and the C allele of CCND1:rs7177 (OR, 1.555; p=0.041) were associated with high tumor histologic grade.ConclusionThe common genetic variants identified in the AKT1, BRCA1, BRCA2, CCND1, CDH1, and NQO2 genes could serve as potential clinical and prognostic biomarkers in sporadic breast cancer patients. Further studies are required to validate our current findings in other populations.

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Nucleotide variants and protein expression of TP53 in a Sri Lankan cohort of patients with head and neck cancer.

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Nucleotide variants and protein expression of TP53 in a Sri Lankan cohort of patients with head and neck cancer.

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