Unfavorable Genotypes Research Articles

FUNCTIONAL AND MOLECULAR-GENETIC REACTIONS UNDER CONDITIONS OF CONDUCTING HEALTH PROGRAMS IN PERSONS WITH EXCESSIVE BODY MASS

In a study of 116 healthy and obese patients (20-63 years), authors have made an assessment of the functional and molecular genetic effects of the health program, which included caloric restriction of food up to 1,000-1,200 calories per day, or a complete rejection of food within 19-21 days, intestinal cleansing, physical exercising in the way of walking 3-7 kilometers per day, laser therapy, body massage, infrared sauna, etc., educational lectures, sessions of spiritual music. The healthy course had been accompanied by loss of total and fat mass, normalization of hemodynamic parameters, cholesterol, leptin, insulin and glucose levels, decrease in insulin- and leptin-resistance. Molecular genetic studies have shown that genotype T23525T of FTO gene is the most unfavorable genotype for residents of the North Caucasus, increasing the risk of developing obesity 2.33-4.90 times. This genotype reliably correlated with the body mass index, weight, the initial fat mass, and the hip circumference. However, the presence of this genotype did not prevent the loss of body weight and fat during the process of health improvement measures. In addition, the phenomenon of transversion of nucleotides (A → T) was detected at the corresponding site of 23525 intron mutations (rs9939609). The established effect shows the possibility of targeted effects on the human genome through health programs. The mechanisms of transversion require explanations and further studies.

Genetic variants in the platelet-derived growth factor subunit B gene associated with pancreatic cancer risk.

The platelet-derived growth factor (PDGF) signaling pathway plays important roles in development and progression of human cancers. In our study, we aimed to identify genetic variants of the PDGF pathway genes associated with pancreatic cancer (PC) risk in European populations using three published genome-wide association study datasets, which consisted of 9,381 cases and 7,719 controls. The expression quantitative trait loci (eQTL) analysis was also performed using data from the 1000 Genomes, TCGA and GTEx projects. As a result, we identified two potential susceptibility loci (rs5757573 and rs6001516) of PDGFB associated with PC risk [odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.05-1.16, and p = 4.70×10-5 for the rs5757573 C allele and 1.21, 1.11-1.32, and 2.01×10-5 for the rs6001516 T allele]. Haplotype analysis revealed that the C-T haplotype carriers had a significantly increased risk of PC than those carrying the T-C haplotype (OR = 1.23, 95% CI = 1.12-1.34, p =5.00 × 10-6 ). The multivariate regression model incorporating the number of unfavorable genotypes (NUGs) with age and sex showed that carriers with 1-2 NUGs, particularly among 60-70 age group or males, had an increased risk of PC, compared to those without NUG. Furthermore, the eQTL analysis revealed that both loci were correlated with a decreased mRNA expression level of PDGFB in lymphoblastoid cell lines and pancreatic tumor tissues (p = 0.015 and 0.071, respectively). Our results suggest that genetic variants in PDGFB may play a role in susceptibility to PC. Further population and functional validations of our findings are warranted.

Polymorphisms in matrix metalloproteinases 2, 3, and 8 increase recurrence and mortality risk by regulating enzyme activity in gastric adenocarcinoma

The association of polymorphisms in matrix metalloproteinases (MMPs) with clinical outcomes of gastric adenocarcinoma has not been examined. Ten polymorphisms in MMP1, 2, 3, 7, 8, 9, 12, and 13 were genotyped and investigated, and patients were followed for an average of 58 months. The activities of MMP2, 3, and 8 were measured. Recurrence risk increased in patients with the MMP2 rs2285053 CC genotype (hazard ratio [HR], 1.85), MMP3 rs679620 AA genotype (HR, 2.15), and MMP8 rs1940475 TT genotype (HR, 2.22) on recurrence free survival (RFS). Co-presence of the unfavorable MMP2 rs2285053 CC and MMP8 rs1940475 TT genotypes resulted in an additional increased risk of recurrence (RFS: HR, 4.42; 95% confidence interval [CI], 2.15–9.09; p<0.0001) and risk of death (overall survival ( OS) : HR, 6.59; 95% CI, 3.15–13.19; p<0.0001). Theoretical survival tree analysis revealed that recurrence-free survival significantly varied from 15.5 to 87 months among patients with different polymorphisms in MMP2, 3, and 8. The enzymatic activities of MMP2 and MMP3 increased (MMP2 rs2285053 CC: 888.60 vs. CT: 392.00, p <0.0001; MMP3 rs679620 AA: 131.10 vs. GG: 107.74, p=0.015), whereas those of MMP8 decreased (MMP8 rs1940475 TT: 133.78 vs. CC: 147.54, p=0.011) in gastric cancer tissues. These results suggest that polymorphisms in MMP2, 3, and 8 may increase cancer recurrence and patient death by increasing or decreasing enzyme activity in patients with gastric adenocarcinoma.

Influence of rare alleles of β‐carotene hydroxylase and lycopene epsilon cyclase genes on accumulation of provitamin A carotenoids in maize kernels

AbstractVitamin A deficiency is one of the major health problems worldwide. Traditional yellow maize possesses very low provitamin A (proA) concentration in endosperm. The influence of rare alleles of β‐carotene hydroxylase (crtRB1) and lycopene epsilon cyclase (lcyE) genes capable of enhancing proA concentration was studied in four BC2F2 populations generated using subtropical inbreds and CIMMYT‐HarvestPlus lines. The occurrence of severe segregation distortion for crtRB1 gene was observed, while lcyE gene was segregated as per Mendelian ratio. Genotype with favourable allele of crtRB1 (CC) had a significant effect on β‐carotene (BC) (7.9‐fold), β‐cryptoxanthin (BCX) (twofold) and proA (5.5‐fold) accumulation, compared to unfavourable genotype (C+C+). Genotype with favourable allele of lcyE (LL) showed 2.1‐fold, 1.6‐fold and twofold significant enhancement in BC, BCX and proA, respectively, over unfavourable genotype (L+L+) in pooled analysis. Of the nine genotypes, double homozygote (CC/LL) had the highest mean BC (12.60 μg/g), BCX (4.44 μg/g) and proA (14.82 μg/g), and combined effect was significantly better than individual gene effects or any other combinations. The information generated here would be useful in designing strategy for proA enrichment in subtropical maize.

Overexpressed Fatty Acid Synthase in Gastrointestinal Stromal Tumors: Targeting a Progression-Associated Metabolic Driver Enhances the Antitumor Effect of Imatinib.

Purpose: In gastrointestinal stromal tumors (GIST), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN).Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNAi or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivoResults:FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (P < 0.0001). FASN overexpression was associated with a nongastric location (P = 0.05), unfavorable genotype (P = 0.005), and increased risk level (P < 0.001) and independently predicted shorter disease-free survival (P < 0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and resensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RPS6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT phosphorylation, Ki-67, and phosphorylated PI3K/AKT/mTOR levels and increased TUNEL labeling.Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs. Clin Cancer Res; 23(16); 4908-18. ©2017 AACR.

Polymorphisms in genes related to epithelial-mesenchymal transition and risk of non-small cell lung cancer.

The epithelial-mesenchymal transition (EMT) process is a crucial step for tumor invasion and metastasis. Previous research investigating EMT has mostly focused on its role in cancer progression. Recent studies showed that EMT and EMT-driving transcription factor (EMT-TF) expression are early events in lung cancer pathogenesis, implying a potential association between EMT and lung cancer risk. In this study, we examined whether genetic variants in EMT-related genes are associated with risk of non-small cell lung cancer (NSCLC). We used data from a genome-wide association study of 1482 NSCLC cases and 1544 healthy controls as the discovery phase, in which we analyzed 1602 single-nucleotide polymorphisms (SNPs) within 159 EMT-related genes. We then validated the significant SNPs in another 5699 cases and 5815 controls from the National Cancer Institute lung cancer genome-wide association study. Cumulative effects were evaluated for validated SNPs, and a gene-based test was performed to explore gene-level association with disease risk. In the discovery phase, 174 SNPs demonstrated significant associations with NSCLC risk. In the validation phase, seven SNPs mapped to EGFR, NOTCH3, ADGRF1 and SMAD3 were confirmed. Cumulative effect analysis of the significant SNPs demonstrated increasing risk with the number of unfavorable genotypes in the discovery and validation datasets. Gene-based analysis implicated ADGRF1, NOTCH3 and CDH1 as significant for NSCLC risk. Functional prediction revealed several potential mechanisms underlying these associations. Our results suggest that EMT-related gene variants may be involved in susceptibility to NSCLC; if confirmed, they might help identify higher-risk individuals.

Abstract 1275: Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility

Abstract Cancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatics analyses, The Cancer Genome Atlas (TCGA) project has recently identified panels of genetic mutations that contributed to or associated with the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these highly mutated genes and lung cancer susceptibility. In this multi-phase study, we aimed to comprehensively evaluate the 1655 tagSNPs located in the 127 significantly mutated genes (SMGs) identified by TCGA, and test their association with risk of lung cancer in a total of 7355 patients and 7301 healthy controls. We found that 11 SNPs in 8 genes showed consistent association (P&amp;lt;0.1) and 8 SNPs significantly associated with lung cancer risk (P&amp;lt;0.05) in both discovery and validation phases. The most significant SNP A was associated with a decreased risk of lung cancer (OR=0.91, 95%CI: 0.87-0.96, P=2.3×10-4). Cumulative analysis of the 11 SNPs showed consistently elevated risk with increasing number of unfavorable genotypes (P for trend=1.2×10-10). In stratified analyses, the association of SNP A and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The eQTL-analysis indicated that genotypes of four SNPs significantly correlated with the expression of their genes respectively. From TCGA data, expression of the identified genes were significantly different in lung tumors compared with normal tissues, and the genes’ highest mutation frequency was found in lung cancers. Integrative pathway analysis (IPA) indicated the identified genes were mainly involved in major cell cycle regulatory pathway suggesting the underlying biological processes. In summary, this study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development. Citation Format: Liren Zhang, Yanwei Zhang, Rong Li, David W. Chang, Yuanqing Ye, John D. Minna, Jack A. Roth, Baohui Han, Xifeng Wu. Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1275. doi:10.1158/1538-7445.AM2017-1275

Genetic variants of cell cycle pathway genes predict disease-free survival of hepatocellular carcinoma.

Disruption of the cell cycle pathway has previously been related to development of human cancers. However, associations between genetic variants of cell cycle pathway genes and prognosis of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we evaluated the associations between 24 potential functional single nucleotide polymorphisms (SNPs) of 16 main cell cycle pathway genes and disease‐free survival (DFS) of 271 HCC patients who had undergone radical surgery resection. We identified two SNPs, i.e., SMAD3 rs11556090 A>G and RBL2 rs3929G>C, that were independently predictive of DFS in an additive genetic model with false‐positive report probability (FPRP) <0.2. The SMAD3 rs11556090G allele was associated with a poorer DFS, compared with the A allele [hazard ratio (HR) = 1.46, 95% confidential interval (95% CI) = 1.13–1.89, P = 0.004]; while the RBL2 rs3929 C allele was associated with a superior DFS, compared with the G allele (HR = 0.74, 95% CI = 0.57–0.96, P = 0.023). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had a significant shorter DFS (P trend = 0.0001). Further analysis using receiver operating characteristic (ROC) curves showed that the model including the NUGs and known prognostic clinical variables demonstrated a significant improvement in predicting the 1‐year DFS (P = 0.011). Moreover, the RBL2 rs3929 C allele was significantly associated with increased mRNA expression levels of RBL2 in liver tissue (P = 1.8 × 10−7) and the whole blood (P = 3.9 × 10−14). Our data demonstrated an independent or a joint effect of SMAD3 rs11556090 and RBL2 rs3929 in the cell cycle pathway on DFS of HCC, which need to be validated by large cohort and biological studies.

Predictive assessment in pharmacogenetics of Glutathione S-transferases genes on efficacy of platinum-based chemotherapy in non-small cell lung cancer patients

The influences of glutathione s-transferase P1, M1, and T1 variants on the efficacy of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients were inconsistent in previous studies. Our meta-analysis enrolled 31 publications including 5712 patients and provided more convincing and reliable conclusions. Results showed that GSTP1 IIe105Val IIe/Val and Val/Val Asian patients were more likely to have better response rates compared to IIe/IIe patients (odds ratio (OR) = 1.592, 95% confidence intervals (CIs), 1.087–2.332, P = 0.017). The Asian patients bearing the favorable GSTM1 null genotype were more likely to have better response rates to platinum-based chemotherapy compared to those patients with the unfavorable GSTM1 present genotype (OR = 1.493 (1.192–1.870), P < 0.001). Caucasian lung cancer patients bearing GSTT1 null genotype might be more closely associated with shorter survival time and higher risks of death than the GSTT1 present patients (hazard ratio (HR) = 1.423, CI = 1.084–1.869, P = 0.011). Our meta-analysis suggested that the GSTP1 IIe105Val, GSTM1 and GSTT1 null variants might be predictive factors for the efficacy of platinum-based chemotherapy to NSCLC patients. The use of GSTP1 IIe105Val, GSTM1 and GSTT1 null polymorphisms as predictive factors of efficacy of personalized platinum-based chemotherapy to NSCLC patients requires further verification with multi-center, multi-ethnic and large-sample-size pharmacogenetic studies.

Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma-specific survival.

Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases-related genes and cutaneous melanoma-specific survival (CMSS) by re-analyzing a published melanoma genome-wide association study (GWAS) and validating the results in another melanoma GWAS. In the single-locus analysis of 36,018 SNPs in 129 Rho-related genes, 427 SNPs were significantly associated with CMSS (p < 0.050 and false-positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e., RHOU rs10916352 G > C, ARHGAP22 rs3851552 T > C, ARHGAP44 rs72635537 C > T and ARHGEF10 rs7826362 A > T) were independently predictive of CMSS (a meta-analysis derived p = 9.04 × 10-4 , 9.58 × 10-4 , 1.21 × 10-4 and 8.47 × 10-4 , respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (ptrend =1.47 × 10-7 and 3.12 × 10-5 ). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five-year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (p = 1.8 × 10-6 ) and ARHGAP22 (p = 5.0 × 10-6 ), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment.

Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy.

This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy. Overall, 530 Japanese patients who were infected with hepatitis C virus genotype 1 received SOF/LDV therapy for 12 weeks, and resistance-associated variants (RAVs) in the hepatitis C virus non-structural protein (NS)5A and NS5B regions were assessed at baseline and virological relapse by direct sequencing. Sustained virological response (SVR) rates did not significantly differ between patients with and without NS5A Y93H/N (94.2% [113/120] vs. 97.7% [345/353]), but the SVR rate was significantly lower in patients with prior DCV/ASV therapy compared to those without (69.2% [18/26] vs. 98.4% [496/504], P <0.001). Among 26 patients with prior DCV/ASV therapy, the prevalence of NS5A multi-RAVs (≥2) was similar between responders and non-responders (61% [11/18] vs. 75% [5/8]), but all patients without RAVs achieved SVR. Multivariate analysis showed that prior DCV/ASV therapy and history of hepatocellular carcinoma were independently associated with treatment failure (odds ratio, 37.55; 95% confidence interval, 10.78-130.76; P <0.001 for prior DCV/ASV therapy; odds ratio, 4.42; 95% confidence interval, 1.09-18.04; P = 0.03 for the history of HCC). All SOF/LDV failure patients (n = 8) with prior DCV/ASV treatment had two or more factors of cirrhosis, IL28B unfavorable genotype, and baseline NS5A multi-RAVs. The multiple NS5A RAVs had increased but NS5B substitutions, C316N/A207T/A218S or L159F, had not changed at the time of relapse. Prior DCV/ASV therapy is associated with failure of SOF/LDV therapy due to multiple RAVs.

ACTH and Polymorphisms at Steroidogenic Loci as Determinants of Aldosterone Secretion and Blood Pressure.

The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by data from genome-wide association studies that consistently link the CYP17A1 locus to blood pressure. In this review article, we describe common polymorphisms at three steroidogenic loci (CYP11B2, CYP11B1 and CYP17A1) that alter gene transcription efficiency and levels of key steroids, including aldosterone. However, the mechanism by which this occurs remains unclear. While the renin angiotensin system is rightly regarded as the major driver of aldosterone secretion, there is increasing evidence that the contribution of corticotropin (ACTH) is also significant. In light of this, we propose that the differential response of variant CYP11B2, CYP11B1 and CYP17A1 genes to ACTH is an important determinant of blood pressure, tending to predispose individuals with an unfavourable genotype to hypertension.

Role of serum level and genetic variation of IL-28B in interferon responsiveness and advanced liver disease in chronic hepatitis C patients.

Interleukin-28B (IL-28B) is suspected to be associated with response to treatment and one of the basic immunological backgrounds in liver transplant candidate (LTC). We aimed to assess whether genotypes of IL-28B can play a role in therapeutic response or advanced stages of liver disease. A total of 364 subjects were genotyped for IL-28B rs12979860 and rs8099917 SNPs using PCR-RFLP assay. Moreover, IL-28 serum level, HCV loads, and genotype were performed. A significant increase was observed in the frequencies of unfavorable rs12979860 genotypes/CT + TT in the chronic hepatitis C (CHC) and LTC groups. In the case of rs8099917, CHC group had a significantly higher frequency of unfavorable genotypes/GT + GG compared to the healthy group. IL-28B serum level was also significantly higher in healthy group compared with the CHC and LTC groups. There were no differences in the distribution of the IL-28B genotypes and haplotypes between responder and non-responder patients. Our results suggest, for the first time, that unfavorable rs12979860 genotypes can be considered one of the important immunological backgrounds in the Iranian LTC population that was confirmed with the lower IL-28 serum level compared to healthy group. Besides, there was a possible association of favorable IL-28B genotypes with lower odds of susceptibility to CHC infection but no support for a positive association between analyzed SNPs and an outcome of therapy. Moreover, non-CT haplotypes may be regarded as a genetic risk factor that can increase the chance of infection with HCV and progression toward end-stage HCV-related liver disease.

PLCB4 copy gain and PLCß4 overexpression in primary gastrointestinal stromal tumors: Integrative characterization of a lipid-catabolizing enzyme associated with worse disease-free survival.

To explore the implications of lipid catabolism-associated genes in gastrointestinal stromal tumors, we reappraised transcriptomic and genomic datasets and identified copy-gained and differentially upregulated PLCB4 gene associated with tumor progression. On full sections, PLCB4 mRNA abundance and PLCß4 immunoexpression were validated in 70 cases. On tissue microarrays, PLCB4 gene copies and PLCß4 immunoexpression were both informative in 350 cases with KIT/PDGFRA/BRAF genotypes noted in 213. In GIST48 cell line, we stably silenced PLCB4 and YAP1 to characterize their functional effects and regulatory link. Compared with normal tissue, PLCB4 mRNA abundance significantly increased across tumors of various risk levels (p<0.001), and was strongly correlated with immunoexpression level (p<0.001, r=0.468). Including polysomy (12.6%) and amplification (17.4%), PLCB4 copy gain was detected in 105 (30%) cases and significantly more frequent (p<0.001) in cases exhibiting higher PLCß4 immunoexpression (82/175). Copy gain and protein overexpression were modestly associated with unfavorable genotypes (both p<0.05), strongly associated with increased size, mitosis, and risk levels defined by both the NIH and NCCN schemes (all p<0.001), and univariately predictive of shorter disease-free survival (both p<0.0001). In PLCß4-overexpressing cases, PLCB4 copy gain still predicted worse prognosis (p<0.0001). In a multivariate comparison, both overexpression (p=0.007, hazard ratio: 2.454) and copy gain (p=0.031, hazard ratio: 1.892) exhibited independent impact. In vitro, YAP1 increased PLCB4 mRNA and protein expression, and both molecules significantly promoted cell proliferation. Being driven by copy gain or YAP1, PLCß4 is a novel overexpressed enzyme regulating lipid catabolism that promotes cell proliferation and independently confers a worse prognosis.

Hypoxia pathway genetic variants predict survival of non-small-cell lung cancer patients receiving platinum-based chemotherapy

Hypoxia is a hallmark of solid tumors and has been implicated in the development of advanced disease and poor clinical outcome. In this multi-stage study, we aimed to assess whether genetic variations in hypoxia pathway genes might affect overall survival (OS) in patients with advanced-stage non-small cell lung cancer (NSCLC). We genotyped 598 potentially functional and tagging single nucleotide polymorphisms (SNPs) in 42 genes of the hypoxia pathway in 602 advanced stage NSCLC patients who received platinum-based chemotherapy or chemoradiation (discovery phase). Significant SNPs were validated in an additional 278 advanced stage patients (validation phase). Cox proportional hazard regression analysis was used to evaluate the association of each SNP with OS. Results showed in chemotherapy only group the median survival time (MST) of NSCLC patients with RPA1: rs2270412 AA+GA genotype versus GG genotype was 10.5 versus 12.7 month [P = 0.004, hazard ratio (HR) = 1.42, 95% CI: 1.16-1.74, combined set]. The MST of patients with EXO1: rs9350 GA+AA genotype versus GG genotypes was 13.2 months versus 11.5 months (P = 0.009, HR = 0.70, 95% CI: 0.56-0.87, combined set). Patients harboring two unfavorable genotypes had a 2.02-fold increased risk of death (P = 3.16E-6) and chemoradiation would improve survival for them (HR = 0.75, 95% CI: 0.51-1.10, P = 0.27, combined set). The MST for patients with 0, 1, and 2 unfavorable genotypes was 13.2, 12.7 and 8.9 months, respectively (P = 0.0002, combined set). In summary, two variants in RPA1 and EXO1 were associated with poor survival in NSCLC patients treated by platinum-based chemotherapy. Adding radiotherapy could improve survival in patients harboring these risk genotypes.

The Synergistic Effect of TNFα -308 G/A and TGFβ1 -509 C/T Polymorphisms on Hepatic Fibrosis Progression in Hepatitis C Virus Genotype 4 Patients.

Tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta (TGFβ1) cytokines are highly implicated in liver fibrosis. Polymorphisms in these cytokines affect their expression, secretion, and activity. This study aimed to evaluate the influence of TNFα -308 G/A and TGFβ1 -509 C/T polymorphism on hepatic fibrosis progression in Egyptian patients with hepatitis C virus (HCV) genotype 4. Genotyping of TNFα -308 G/A and TGFβ1 -509 C/T was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 122 subjects (50 healthy controls and 72 HCV patients). Also, serum TNFα and TGFβ1 levels were detected by enzyme-linked immunosorbent assay (ELISA). The genotyping results of early (F0-F1, n = 36) and late (F2-F4, n = 36) HCV fibrosis patients showed that late fibrosis patients had higher TNFα -308 AA genotype and TGFβ1 -509 TT genotype than early fibrosis patients (p = 0.016, 0.028, respectively). Moreover, the TNFα and TGFβ1 serum levels were significantly higher in HCV patients with TNFα A containing genotypes (GA+AA) (p = 0.004) and patients with TGFβ1 T containing genotypes (CT+TT) (p = 0.001), respectively. The combined unfavorable TNFα (GA/AA) and TGFβ1 (CT/TT) genotypes were highly associated with abnormal liver function parameters and were significantly higher in high activity (A2-A3) and late fibrosis (F2-F4) HCV patients (p = 0.023, 0.029). The multivariate analysis results confirmed that the combined TNFα-308 (AA) and TGFβ1 -509 (TT) unfavorable genotypes increased the risk of hepatic fibrosis progression by 6.4-fold than combined favorable genotypes (odds ratio: 6.417, 95% confidence interval [1.490-27.641], p = 0.013). In conclusion, both TNFα -308 G/A and TGFβ1 -509 C/T polymorphisms synergistically influence the hepatic fibrosis progression and can be used as potential biomarkers to predict hepatic disease progression in chronic hepatitis C patients.

Selection of experimental strawberry (Fragaria x ananassa) hybrids based on selection indices.

The strawberry (Fragaria x ananassa Dutch.), is the only vegetable belonging to the rosacea family. All strawberry species have now emerged from wild species and belong to the genus Fragaria, being that this genus presents more than 45 described species, and only 11 are considered natural species. Due to the octoploid nature of strawberry and its variability after hybridization, selecting one or more characters may result in unfavorable genotypes and even the exclusion of promising ones, because negative genetic correlations have been observed among them that cause inefficient selection. Therefore, the objective of this study was to verify the efficiency of selection indices in selecting experimental strawberry hybrids for in natura consumption and processing. Seven commercial cultivars and 103 hybrids were used, which were obtained from populations derived from their crossings. The experiment was conducted in augmented blocks, in which four agronomical traits (total mass, amount of commercial fruit, amount of noncommercial fruit, and average fruit mass) and seven physical-chemical traits (soluble solids, soluble solids:titratable acidity ratio, total sugars, total pectin, vigor, and internal and external coloration) were evaluated. For hybrid selection, the following indices were used: Mulamba and Mock (1978), Smith (1936), Hazel (1943), and genotype-ideotype, which selected 20% of the genotypes evaluated. The three indices selected about 9% of the hybrids. The selection of two experimental hybrids (89 and 495) and the use of selection indices resulted in larger estimates of selection gains. The Mulamba and Mock (1978), Smith (1936), and Hazel (1943) indices had the highest percentage of gains on selection, and are therefore recommended for the selection of strawberry clones.

Influence of Cytochrome P450, ABC and SLC Gene Polymorphisms on Imatinib Therapy Outcome of Patients with Gastrointestinal Stromal Tumours (GIST)

The efficacy of imatinib-based therapy depends on the proteins involved in its metabolism and transportation. Therefore, the aim of our study was to investigate the possible correlation of selected P450, ABC and SLC polymorphic variants and the outcome of imatinib therapy. A total of 101 patients with advanced, KIT/PDGFRA(+) GIST treated with imatinib were enrolled to the study. DNA was extracted from peripheral blood samples and genotypes were determined by PCR-RFLP and direct sequencing. Deviation from the Hardy-Weinberg equilibrium was only observed for rs2740574. None of the studied SNPs was associated with GIST time to progression. No significant correlation between any specific variant and time to progression was found in the group with KIT exon 11 mutation. However, individuals of at least three potentially unfavourable genotypes presented significantly shorter time to progression in comparison to patients with two or less unfavourable genotypes.

MicroRNA-Related Polymorphisms in PI3K/Akt/mTOR Pathway Genes Are Predictive of Limited-Disease Small Cell Lung Cancer Treatment Outcomes

The phosphoinositide-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in cancer progression and treatment, including that of small cell lung cancer (SCLC), a disease with traditionally poor prognosis. Given the regulatory role of microRNA (miRNA) in gene expression, we examined the association of single nucleotide polymorphisms (SNPs) at miRNA-binding sites of genes in the mTOR pathway with the prognosis of patients with limited-disease SCLC. A retrospective study was conducted of 146 patients with limited-disease SCLC treated with chemoradiotherapy. Nine SNPs of six mTOR pathway genes were genotyped using blood samples. Cox proportional hazard regression modeling and recursive partitioning analysis were performed to identify SNPs significantly associated with overall survival. Three SNPs, MTOR: rs2536 (T>C), PIK3R1: rs3756668 (A>G), and PIK3R1: rs12755 (A>C), were associated with longer overall survival. Recursive partitioning analysis based on unfavorable genotype combinations of the rs2536 and rs3756668 SNPs classified patients into three risk subgroups and was internally validated with 1000 bootstrap samples. These findings suggest that miRNA-related polymorphisms in the PI3K/Akt/mTOR pathway may be valuable biomarkers to complement clinicopathological variables in predicting prognosis of limited-disease SCLC and to facilitate selection of patients likely to benefit from chemoradiotherapy.

THE PATHOGENETIC SIGNIFICANCE OF GENE IL28B POLYMORPHISMS AT SITES RS12979860 AND RS8099917 IN THE DEVELOPMENT OF CHRONIC VIRAL HEPATITIS C IN PATIENTS OF THE SOUTH-EASTERN REGION OF BELARUS

To study the role of IL28B gene polymorphisms in the development of chronic hepatitis C, we have determined polymorphic types of the gene at sites rs12979860 and rs8099917 using allele-specific polymerase chain reaction with real-time product detection in 21 patients with this disease. We have found the association of chronic hepatitis C with the presence of unfavorable TT genotype of gene IL28B polymorphism rs12979860, which can be regarded as a predictor of the development of this pathology. Favorable genotypes of CC rs12979860 and TT polymorphism of rs8099917 of gene IL28B are more common in healthy individuals and they are associated with higher activity of the inflammatory process in patients with chronic hepatitis C. Therefore, gene IL28B polymorphisms can affect not only the outcome of an acute viral infection but also the further course of chronic hepatitis C.