International journal of molecular epidemiology and genetics最新文献

The alternative splicing plays an important role to generate protein diversity. Recent studies have shown alterations in alternative splicing, resulting in loss, gain or changes of functions in the resulting protein. Specific products of alternative splicing are known to contribute in cancer-related mechanisms, such as angiogenesis, migration, adhesion and cell proliferation, among others. We using high-density microarrays reported a CENP-E as a one of significant transcript expressed and potentially is alternatively spliced in cancer. We focus in validate alternative splicing of CENP-E transcript using RT-PCR and sequencing in different cancer cell lines. We performed RT-PCR using specific primers designed to delimit the non-reported alternative splicing in CENP-E transcript. Our results showed the co-expression of the variant one and two of CENP-E in all cell lines evaluated. We detected more expression of variant one than two. Moreover, we identify an alternative 5'splice site of CENP-E in the exon 38 and was observed in RoVa cell line. Additionally, we characterized alternative skipping from exon 20 (NAT-CENP-E), these alternative splicing was observed in all cell lines evaluated except RoVa. Finally, we corroborate alternative mRNA splicing in leukemia patients using quantitative RT-PCR, in 71.8% of the patients NAT-CENP-E is downregulated and 28.2% is overexpressed.

The genetic load and diversity of monogenic hereditary diseases (HD) in the Russian population of Karachay-Cherkess Republic (KCHR), living in 10 administrative and municipal divisions, were studied. The total size of the population surveyed was 410,367 people, including 134,756 Russians. In total, 385 patients from 281 families were registered among Russians of KCHR. Genetic load of AD, AR, and X-linked diseases (3.01 ± 0.32, 1.98 ± 0.26, and 1.23 ± 0.29, respectively) are more than twice higher in cities and municipal centers than in corresponding rural regions (1.00 ± 0.10, 0.89 ± 0.09, and 0.42 ± 0.09, respectively). The diversity of HD was 96 nosological forms: 56 diseases with AD type of inheritance (193 patients from 126 families), 28 clinical forms with AR (152 patients out of 124 families) and 12 diseases with the X-linked type of inheritance (40 affected from 31 families). A comparative analysis of the diversity of AD and AR HD with the previously studied populations and ethnic groups of the European part of Russia (Russians of 7 regions, 5 peoples of the Volga-Ural region, and 5 populations of the North Caucasus) was conducted, showing that Russians in the KCHR preserved genetic load with other Russian populations and its difference from the same mutation pool of Karachays and Circassians.

Breast cancer is a complex disease. Single Nucleotide Polymorphisms (SNPs) can modify the risk of cancer. They may be regarded as potential markers of carcinogenesis. Currently, the diversity or polymorphism of ERCC5 gene (excision repair cross-complementary group 5 gene or ERCC5) was reported to associate with an increased risk of breast cancer. This study aims to investigate the relationship between ERCC5 polymorphism and the breast cancer risk in the lower northeastern region women of Thailand. One hundred fifty five samples from breast cancer patients and 122 samples from healthy control group were analysed. Genomic DNA was extracted from white blood cell of all samples. The real-time polymerase chain reaction (qPCR) was used to demonstrate genetic polymorphism of ERCC5. The results showed that the ERCC5 rs751402 polymorphism variant AG was associated with an increased risk of breast cancer. The frequency of ERCC5 rs751402 in patients with breast cancer was higher than healthy control group. The ERCC5 rs751402 variant AG carrier was associated with increased breast cancer risk to 2.3 folds, with OR = 2.30, 95% CI = 1.22-4.35, P = 0.01, when age, menopause period, number of child, smoking and alcohol drinking were adjust. This study demonstrated that ERCC5 rs751402 genotype AG was associated with breast cancer risk in the lower northeastern region women of Thailand.

Nitric oxide (NOx) availability in biological systems is associated with either favorable or unfavorable outcomes. In this sense, several studies bring about evidence that unbalanced NOx production may be underlying to the pathophysiology of vascular disorders. Our study investigated the possible association of clinical, biochemical and inflammatory variables with total circulating levels of NOx in elderly patients devoid of major inflammatory conditions. Clinical (demographics, lifestyle, anthropometry, pressoric traits) and biochemical characteristics (lipemic, glycemic and hormonal profiles) were assessed from 168 geriatrics outpatients eligible for primary care for age-related disorders. Furthermore, circulating levels of 10 inflammatory mediators and of NOx were measured. Correlation tests analyzed categorical or continuous traits according to serum NOx and found no association between NOx and any of the clinical or laboratory data but a negative correlation between plasma NOx concentrations and levels of the immune mediator IL17a (r = -0.236; P = 0.004). Evidence for a correlation between circulating NOx and IL17 is already present in the literature, mostly from studies conducted under inflammatory conditions. Our hypothesis is that such negative correlation can be attributed to an endogenous homeostatic system that IL17 production by the constitutively produced NOx from the vascular endothelium.

Hepatic steatosis is a common finding in liver biopsy and may co-exist with chronic hepatitis B (CHB) infection. The aims of this study were to determine the prevalence of steatosis in CHB patients among Filipinos; determine the factors related to the presence of steatosis among individuals with and without CHB infection; and to investigate the possible association between steatosis and polymorphism in interleukin 28B (IL28B) gene. The presence of steatosis was correlated with clinical, biochemical and histological parameters. Peripheral blood samples of CHB patients with steatosis, CHB patients without steatosis and normal controls were genotyped for IL28B rs8099917 T>G using the TaqMan assay. Of the 46 CHB patients, 41% (19/46) had steatosis. Body mass index (BMI), fasting blood sugar (FBS), lipid profile and alanine transaminase levels were observed to be significantly different between CHB patients with steatosis and normal controls. The serum FBS of CHB patients with steatosis was significantly higher than patients without steatosis. High density lipoprotein cholesterol of patients without steatosis was significantly higher than patients with steatosis. Although not statistically significant, BMI, triglycerides, low density lipoprotein cholesterol and histology activity index in CHB patients with steatosis were found to be higher than those without steatosis. There was no significant association between the stage of fibrosis and severity of steatosis. In conclusion, the prevalence of hepatic steatosis among Filipino patients with CHB is 41%. Steatosis in CHB patients was associated with metabolic factors such as diabetes and dyslipidemia. IL28B rs8099917 T>G polymorphism is not associated with steatosis.

Purpose: The primary purpose of this study was to clinically evaluate circulating tumor DNA (ctDNA) with a nine gene, 96 mutation panel among subjects at increased risk for cancer with no previous cancer diagnosis.

Subjects and methods: DNA from 1059 asymptomatic subjects was analyzed for detection of low levels ctDNA using a blood plasma liquid biopsy assay. Subjects with detectable copies of ctDNA were asked to provide additional blood samples and relevant medical records throughout their one-year of participation. Subjects with a negative result were followed-up at one-year with a questionnaire.

Results: Mutations were detected in 58 subjects and not detected in 1001 subjects. Among the subjects who tested positive for one or more mutations, four were diagnosed with cancer, two of which through study-triggered clinical follow-up. Two subjects who tested negative on the screen received an early cancer diagnosis over the course of the year. The sensitivity of the assay at a threshold of ≥2 copies in this population was 66.67% and specificity was 94.87%. While the negative predictive value was 99.8%, the positive predictive value was only 6.9% in this cohort. Analysis of buffy coat DNA from eight positive subjects, including one who was diagnosed with cancer, revealed matching mutations suggesting that the ctDNA could have been derived from clonal hematopoiesis.

Conclusion: The observed false positive rate of ctDNA on a 96-mutation assay in an asymptomatic high-risk population is much greater than the true positive rate, limiting its usefulness as a cancer screening tool in its current form.

Telomere shortening is associated with colorectal carcinogenesis and recent studies have focused on its characteristics in both normal mucosa and tumor tissues. To clarify the role of telomeres in colorectal carcinogenesis, we analyzed telomere shortening in normal and tumor regions of 93 colorectal precursor lesions. Telomere length was examined in 61 tubular adenomas (TAs) and 32 serrated polyps (SPs), and PIK3CA expression, KRAS mutation, BRAF mutation, and MSI were also analyzed. Telomere length was similar in normal and tumor tissues of TAs and SPs. In normal tissues of TAs, telomere shortening was associated with PIK3CA amplification (81.3% vs. 18.8%, p < 0.001), whereas it was associated with BRAF mutation in normal tissues of SPs (66.7% vs. 23.1%, p = 0.060). According to the analysis on tumor tissues, KRAS and BRAF mutations were mutually exclusive in TAs and SPs (p < 0.001), and telomere shortening was associated with mitochondrial microsatellite instability (63.6% vs. 36.4%, p = 0.030). These data suggested a pivotal role of telomere shortening in normal colorectal tissue for proceeding to TAs or SPs along with PIK3CA amplification and BRAF mutation, respectively. Moreover, telomeres in TAs may collaborate with mitochondrial instability for disease progression.

[This corrects the article on p. 1 in vol. 8, PMID: 28337312.].

The aryl hydrocarbon receptor (AhR) is a transcription factor implicated in several pathways known to be relevant in lymphomagenesis. Aim of our study was to explore the link between AhR activation and risk of lymphoma subtypes. We used a Dual-Luciferase Assay^® and a luminometer to detect the activation of the luciferase gene, in HepG2 cells transfected with a specific reporter systems, by a 50 ml serum aliquot of cases of diffuse large B cell lymphoma (N = 108), follicular lymphoma (N = 85), chronic lymphocytic leukemia (N = 72), multiple myeloma (N = 80), and Hodgkin lymphoma (N = 94) and 357 controls who participated in the multicentre Italian study on gene-environment interactions in lymphoma etiology (ItGxE). Risk of each lymphoma subtype associated with AhR activation was calculated with polytomous logistic regression adjusting by age, gender, and study centre. The overall prevalence of AhR activation ranged 13.9-23.6% by subtype, and it varied by study area (8-39%). Risk associated with AhR activation was moderately elevated for follicular lymphoma (OR = 1.56, 95% CI 0.86, 2.80) and chronic lymphocytic leukemia (OR = 1.56, 95% CI 0.83, 2.96). Despite our inconclusive findings about the association with risk of lymphoma subtypes, we showed that the Dual-Luciferase Assay can be reliably and easily applied in population-based studies to detect AhR activation.

Gastric cancer (GC) is the 5th most prevalent cancer. The etiology of GC is still poorly understood. We performed a case-control study in a Chinese population to investigate the association of rs2243248 (-1098 G/T), rs2227284 (-33 C/T), rs2243250 (-589 T/C) and rs2070874 (-107 T/C) polymorphisms and haplotypes with the development of gastric cancer in a Chinese population. A total of 362 patients with gastric cancer and 384 controls were recruited between December 2013 and December 2015. Genotyping of rs2243248 (-1098 G/T), rs2227284 (-33 C/T), rs2243250 (-589 T/C) and rs2070874 (-107 T/C) was performed in a 384-well plate format on the sequenom MassARRAY platform, and analyzed by MALDI-TOF MS. The TC and CC genotypes of rs2243250 (-589 T/C) were associated with an increased risk of gastric cancer when compared with the TT genotype, with adjusted ORs (95% CI) of 1.52 (1.07-2.15) and 2.13 (1.30-3.51), respectively. The TTTT haplotype revealed a reduced risk of gastric cancer (OR=0.65, 95% CI=0.45-0.94). No linkage disequilibrium was found among IL-4 rs2243248, rs2227284, rs2243250 and rs2070874. In summary, our findings support a significant association of IL-4 rs2243250 polymorphism with the risk of gastric cancer in the Chinese population, and IL-4 haplotype contributes to the development of this disease.