Polymorphisms in MicroRNA‐Related Genes Are Associated With Survival of Patients With T‐Cell Lymphoma

Objective

Elaborate evaluation of prognosis of T-cell lymphoma (TCL) is vital for current therapy and future stratified and individualized therapy. MicroRNAs (miRNAs) play important roles in cancer development and prognosis. We aimed to assess the effects of single nucleotide polymorphisms (SNPs) in miRNA-related genes on the survival of patients with TCL.

Patients and Methods

We genotyped 13 SNPs selected from 12 miRNA-related genes in 220 TCL patients and explored the association of SNPs with survival.

Results

Among the 13 SNPs, four (DROSHA rs6877842, DICER rs3742330, mir149 rs2292832, and mir499 rs3746444) were significantly associated with TCL survival after adjusting for subtype and International Prognostic Index score. In stratified analyses, all four SNPs remained significantly associated with survival in patients with mature T type. Of the four SNPs, only mir149 rs2292832 was not significantly associated with survival in patients with an International Prognostic Index score of 0–1. Furthermore, a dose-dependent cumulative effect of the four SNPs on TCL survival was observed by counting the number of unfavorable genotypes. Survival tree analysis also showed higher order interactions between these SNPs.

Conclusion

The results suggested that miRNA-related polymorphisms are associated with survival of TCL patients; thus, they may be used individually and jointly to predict survival of patients with TCL.     

Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non‐small cell lung cancer in the PLCO cancer screening trial

The tumor necrosis factor (TNF)/TNF receptor (TNFR) pathway is known to influence survival of patients with cancer. We hypothesize that single nucleotide polymorphisms (SNPs) in the TNF/TNFR pathway genes related to apoptosis are associated with survival of patients with non‐small cell lung cancer (NSCLC). We used 1185 patients with NSCLC in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study as the discovery and validation datasets, respectively. We selected 6788 SNPs in 71 genes in the TNF/TNFR signaling pathway and extracted their genotyping data from the PLCO genowide‐association study (GWAS) dataset. We performed Cox proportional hazards regression analysis to evaluate associations between the identified SNPs and survival and validated the significant SNPs, which were further analyzed for their functional relevance. We found that genotypes of two validated SNPs, IKBKAP rs4978754 CT + TT and TNFRSF1B rs677844 TC + CC, as well as their combined genotypes predicted a better overall survival (P = 0.004, 0.002 and <0.001, respectively). These two validated SNPs were predicted by the RegulomeDB score to be potentially functional. In addition, IKBKAP mRNA expression levels were significantly higher, while TNFRSF1B mRNA expression levels were significantly lower in lung cancer tissues than in adjacent normal tissues (P < 0.001). The Cancer Genome Atlas (TCGA)‐based expression quantitative trait loci analysis showed that IKBKAP rs4978754 and TNFRSF1B rs677844 genotypes were significantly associated with their corresponding mRNA expression levels in lung cancer tissues in a recessive model (P = 0.035 and 0.045, respectively). Therefore, we identified two potentially functional SNPs (IKBKAP rs4978754 C > T and TNFRSF1B rs677844 T > C) to be associated with survival of patients with NSCLC.     

B-cell Lymphoma 2 rs17757541 C>G Polymorphism was Associated with an Increased Risk of Gastric Cardiac Adenocarcinoma in a Chinese Population

Aim: Apoptosis has been considered as a fundamental component in cancer pathogenesis, and related geneticfactors might play an important role in gastric cardiac adenocarcinoma (GCA) genesis. Methods: We conducteda hospital based case–control study to evaluate the genetic effects of functional single nucleotide polymorphisms(SNPs): BCL2 rs17757541 C>G, BCL2 rs12454712 T>C, FAS rs2234767 G>A, FASL/FASLG rs763110 C>T,ERBB2 rs1136201 A>G and VEGFR2/KDR rs11941492 C>T on the development of GCA. A total of 243 GCAcases and 476 controls were recruited for the study and genotypes were determined using a custom-by-design48-Plex SNPscanTM Kit. Results: The BCL2 rs17757541 C>G polymorphism was associated with increased riskof GCA. However, there was no significant associations with the other five SNPs. Stratified analyses indicateda significantly increased risk of GCA associated with the BCL2 rs17757541 C>G polymorphism among males,older patients and those with a history of smoking or drinking. Conclusion: These findings indicated that thefunctional polymorphism BCL2 rs17757541 C>G might contribute to GCA susceptibility. However, our resultswere limited by small sample size. Future larger studies are required to confirm our current findings.     

Common Genetic Variants of PSCA,MUC1 and PLCE1 Genes are not Associated with Colorectal Cancer

Background: Polymorphisms of genes encoding PSCA, PLCE1 and MUC1 have been associated with the riskof different cancers in genome wide association studies (GWAS). Up to date there are limited data on the role ofthese genetic alterations in colorectal cancer (CRC) development. The aim of this study was to evaluate potentialassociations between single nucleotide polymorphisms (SNPs) of genes encoding PSCA, PLCE1 and MUC1 andthe presence of CRC in European populations. Materials and Methods: Gene polymorphisms were analyzed in574 European subjects (controls: n=382; CRC: n=192). PSCA C>T (rs2294008), PSCA G>A (rs2976392), MUC1A>G (rs4072037) and PLCE1 A>G (rs2274223) SNPs were genotyped by RT-PCR. Results: The distribution ofgenotypes for all four SNPs was in line with the Hardy-Weinberg equilibrium (rs2294008, P=0.153; rs2976392,P=0.269; rs4072037, P=0.609; rs2274223, P=0.858). The distribution of genotypes and alleles of PSCA C>T,PSCA G>A, MUC1 A>G and PLCE1 A>G SNPs was similar among controls and CRC patient groups (P>0.05).GG genotype of MUC1 SNP was more frequent in CRC patients (24.0%) than in controls (20.2%); however, thisassociation failed to reach significance (OR-1.45, P=0.15). Overall, in the present study SNPs of PSCA (rs2294008,rs2976392), MUC1 (rs4072037) and PLCE1 (rs2274223) genes were not associated with the presence of CRC.Conclusions: Gene polymorphisms of PSCA, PLCE1 and MUC1 genes are not associated with the presence ofCRC in European subjects.     

Epidermal growth factor receptor pathway polymorphisms and the prognosis of hepatocellular carcinoma

The EGFR signaling pathway is important in the control of vital processes in the carcinogenesis of hepatocellular carcinoma (HCC), including cell survival, cell cycle progression, tumor invasion and angiogenesis. In the current study, we aim to assess if genetic variants in the genes of the EGFR signaling pathway are associated with the prognosis of HCC. We genotyped 36 single nucleotide polymorphisms (SNP) in four core genes (EGF, EGFR, VEGF, and VEGFR2) by using DNA from blood samples of 363 HCC patients with surgical resection. The associations between genotypes and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confident intervals (CIs) were estimated for the multivariate survival analyses by Cox proportional hazards regression models, adjusting for age, gender, family history, HBsAg and AFP. We found that five SNPs in the VEGFR2 gene were significantly associated with clinical outcomes of HCC patients. Among them, four SNPs (rs7692791, rs2305948, rs13109660, rs6838752) were associated with OS (p=0.035, 0.038, 0.029 and 0.028, respectively), and two SNPs (rs7692791 and rs2034965) were associated with DFS (p=0.039 and 0.017, respectively). Particularly, rs7692791 TT genotype was associated with both reduced OS (p=0.037) and DFS (p=0.043). However, only one SNP rs2034965 with the AA genotype was shown to be an independent effect on DFS (p=0.009) in the multivariate analysis. None of the other 31 polymorphisms or 9 haplotypes attained from the four genes was significantly associated with OS or DFS. Our results illustrated the potential use of VEGFR2 polymorphisms as prognostic markers for HCC patients.     

Interleukin 10 rs1800872 T>G Polymorphism was Associated with an Increased Risk of Esophageal Cancer in a Chinese Population

Aim: Esophageal cancer is the eighth most common cancer and sixth leading cause of cancer associateddeath worldwide. The 5 year survival rate for esophageal cancer patients is very poor and accounts for only12.3%. Besides environmental risk factors, genetic factors might play an important role in the esophageal cancercarcinogenesis. Methods: We conducted a hospital based case–control study to evaluate the genetic effects offunctional single nucleotide polymorphisms (SNPs): interleukin 9 (IL9) rs31563 C>T, IL9 rs31564 G>T, IL10rs1800872 T>G, IL12A rs2243115 T>G, IL12B rs3212227 T>G and IL13 rs1800925 C>T on the developmentof esophageal cancer. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls wererecruited for this study. The genotypes were determined using a custom-by-design 48-Plex SNPscanTM Kit. Results:The IL10 rs1800872 T>G polymorphism was associated with an increased risk of ESCC. However, there were nosignificant links with the other five SNPs. Stratified analyses indicated no significant risk of ESCC associated withthe IL10 rs1800872 T>G polymorphism evident among any subgroups. Conclusion: These findings indicated thatfunctional polymorphism IL10 rs1800872 T>G might contribute to ESCC susceptibility. However, our resultswere obtained with a limited sample size, so that the power of our analysis was low. Future larger studies withmore rigorous study designs of other ethnic populations are required to confirm the current findings.     

CD44 rs13347 C>T polymorphism predicts breast cancer risk and prognosis in Chinese populations

ABSTRACT: INTRODUCTION: It has been demonstrated that the interplay of adhesion molecule CD44 and its ligands can regulate cancer cell proliferation, migration and invasion, as well as tumor-associated angiogenesis and is related to breast cancer patient survival. In this two-stage, case control study, we determined whether common functional tagSNPs (single nucleotide polymorphisms) are associated with breast cancer risk and prognosis. METHODS: Five tagSNPs of CD44 (rs10836347C>T, rs13347C>T, rs1425802A>G, rs11821102G>A, rs713330T>C) were selected and genotyped in 1,853 breast cancer patients and 1,992 healthy control subjects in Eastern and Southern populations. Potential function of rs13347C>T and association between this variation and breast cancer were further studied. RESULTS: Compared with the most common rs13347CC genotype, variant genotypes (CT and TT) increased an individual's susceptibility to breast cancer, especially in estrogen receptor (ER) negative patients (odds ratio (OR) = 1.37, 95%CI = 1.17 to 1.59 for ER positive patients; OR = 2.37, 95% CI = 2.00 to 2.80 for ER negative patients). We also found that rs13347CT+ TT genotypes predicts lower five-year survival rate (hazard ratio (HR) = 1.85, 95% CI = 1.09 to 3.15, P = 0.023), with the lowest survival probability in ER negative T allele carriers. Furthermore, our reporter assay findings, although preliminary and rather modest, showed that miR-509-3p may suppress CD44 expression more strongly in C allele carriers than T allele carriers (P < 0.01). Similarly, rs13347 variant genotypes (CT and TT) carriers were shown to have more CD44 expression than CC carriers in both immunohistochemistry (P < 0.001) and western blotting (P = 0.001) results. CONCLUSION: These findings suggest that CD44 rs13347C>T polymorphism may affect breast cancer development and prognosis by increasing CD44 expression.     

MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not

The prognostic significance of single-nucleotide polymorphisms (SNPs) and tumour protein levels of MMP-2 and MMP-9 was evaluated in 215 colorectal cancer patients. Single-nucleotide polymorphism MMP-2(-1306T) and high MMP-2 levels were significantly associated with worse survival. Extreme tumour MMP-9 levels were associated with poor prognosis but SNP MMP-9(-1562C>T) was not. Tumour MMP levels were not determined by their SNP genotypes.     

Polymorphisms in DNA repair and apoptosis-related genes and clinical outcomes of patients with non-small cell lung cancer treated with first-line paclitaxel-cisplatin chemotherapy

This study was conducted to analyze a comprehensive panel of single nucleotide polymorphisms (SNPs) in genes in DNA repair and apoptosis pathways and determine the relationship between polymorphisms and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with first-line paclitaxel-cisplatin chemotherapy. Three hundred eighty two patients with NSCLC were enrolled. Seventy-four SNPs in 48 genes (42 SNPs in 27 DNA repair pathway genes and 32 SNPs in 21 apoptotic pathway genes) were genotyped and their associations with chemotherapy response and overall survival (OS) were analyzed. Among SNPs in DNA repair genes, BRCA1 rs799917 was significantly associated with both chemotherapy response and OS. XRCC1 rs25487 exhibited a significant association with chemotherapy response and ERCC2 rs1052555 with OS. Four SNPs in apoptotic genes (TNFRSF1B rs1061624, BCL2 rs2279115, BIRC5 rs9904341, and CASP8 rs3769818) were significantly associated with OS, but not with response to chemotherapy. When the six SNPs which were associated with OS in individual analysis were combined, OS decreased as the number of bad genotypes increased (P_trend = 2 × 10⁻⁶). Patients with 3, and 4–6 bad genotypes had significantly worse OS compared with those carrying 0–2 bad genotypes (adjusted hazard ratio [aHR] = 1.54, 95% CI = 1.14–2.08, P = 0.005; aHR = 2.10, 95% CI = 1.55–2.85, P = 2 × 10⁻⁶, respectively). In conclusion, these findings suggest that the six SNPs identified, particularly their combined genotypes, could be used as biomarkers predicting chemotherapy response and survival of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.     

Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy

DNA repair enzymes repair DNA damaged by platinum agents and ionising radiation. Single nucleotide polymorphisms (SNPs) in DNA repair genes modulate the repair capacity and might affect response and prognosis following platinum-based chemoradiotherapy (CRT). We investigated associations between the functional SNPs in DNA repair genes and response and survival in muscle-invasive bladder cancer patients treated with CRT to determine the predictive value of the SNPs in patient selection for bladder conservation therapy. The study group comprised 78 patients who underwent CRT for transitional cell carcinoma of the bladder. Single nucleotide polymorphisms in xeroderma pigmentosum complementation groups C (Lys939Gln, A/C), D (XPD; Lys751Gln, A/C), and G (Asp1104His, G/C), and X-ray repair cross-complementing groups 1 (XRCC1; Arg399Gln, G/A) and 3 (Thr241Met, T/C) genes were genotyped. Combined genotypes with at least one variant allele in XPD or XRCC1 were significantly associated with improved cancer-specific survival compared with remaining groups (P=0.009). In multivariate analysis, only the combined XPD and XRCC1 genotypes were independently associated with cancer-specific survival (P=0.04). The association was stronger in stage T3/T4 patients (P=0.0008). These results suggest that combined XPD and XRCC1 genotypes might be prognostic factors in muscle-invasive bladder cancer patients treated with CRT.     

Genetic polymorphisms in oxidative stress-related genes are associated with clinical outcome in patients with advanced non-small cell lung cancer receiving tyrosine kinase inhibitors

Many types of cancer have high antioxidant capacity that effectively scavenges reactive oxygen species and thus protect cancer cells against oxidative damage. The aim of this study was to examine the effect of 20 single nucleotide polymorphisms (SNPs) in 20 oxidative stress-related genes on clinical outcome in 219 patients with advanced non-small cell lung cancer (NSCLC) who were treated with EGFR tyrosine kinase inhibitors (TKIs). We assessed the associations of SNPs with prognosis in all patients as well as stratified by clinical characteristics. Three SNP (rs1695, rs2333227 and rs699512) were significantly associated with overall survival (OS). In a multivariate analysis, rs1695 AA and rs2333227 AG/GG genotypes were identified as independent prognostic factors for poor OS. Stratification analyses revealed that these 3 SNPs remained significantly associated with OS. Furthermore, there was a strong gene-dosage effect of these 3 SNPs on OS that patients with increasing number of unfavorable genotypes had significantly increased death risk. In conclusion, our findings provide the first evidence that genetic variants in oxidative stress-related genes may influence treatment outcome in advanced NSCLC patients receiving EGFR TKIs.     

Association of PINX1 but not TEP1 Polymorphisms with Progression to Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B Virus Infection

Hepatocellular carcinoma (HCC) is major health problem with high mortality rates, especially in patients with hepatitis B virus (HBV) infection. Telomerase function is one of common mechanisms affecting genome stability and cancer development. Recent studies demonstrated that genetic polymorphisms of telomerase associated genes such as telomerase associated protein 1 (TEP1) rs1713449 and PIN2/TERF1-interacting telomerase inhibitor 1 (PINX1) rs1469557 may be associated with risk of HCC and other cancers. In this study, 325 patients with HCC and 539 non-HCC groups [193 healthy controls, 80 patients with HBV-related liver cirrhosis (LC) and 266 patients with HBV-related chronic hepatitis (CH)] were enrolled to explore genetic polymorphisms of both SNPs using the allelic discrimination method based on MGB probe TaqMan real time PCR. We demonstrated that all genotypes of both genes were in Hardy-Wienberg equilibrium (>0.05). Moreover, there was no significant association between rs1713449 genotypes and HCC risk, HCC progression and overall survival (>0.05). Interestingly, we observed positive association of rs1469557 with risk of HCC when compared with the LC group under dominant (CC versus CTTT, OR=1.89, 95% CI= 1.06-3.40, P=0.031) and allelic (C versus T alleles, OR=1.75, 95% CI=1.04-2.94, P=0.033) models, respectively. Moreover, overall survival of HCC patients with CC genotype of rs1469557 was significantly higher than non-CC genotype (Log-rank P=0.015). These findings suggest that PINX1 rs1469557 but not TEP1 rs1469557 might play a role in HCC progression in Thai patients with LC and be used as the prognosis marker to predict overall survival in HCC patients.     

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7(-181A>G). In addition, the genotype distribution of MMP-7(-181A>G) was associated with Helicobacter pylori status (chi(2) 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2(303C>T) correlated significantly with the WHO classification (chi(2) 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2(-1306C>T) polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7(-181A>G) and TIMP-2(303C>T) polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7(-181A>G) and TIMP-2(303C>T), may be helpful in identifying gastric cancer patients with a poor clinical outcome.     

Association of MicroRNA 196a and 499 Polymorphisms with Development of Cirrhosis and Hepatocellular Carcinoma Post-HCV Infection in Egyptian Patients

Hepatocellular carcinoma (HCC) is the commonest primary tumor of the liver. Chronic HCV infection is the leading cause of end-stage liver disease, HCC and liver-related death in Egypt. Single nucleotide polymorphisms (SNPs) in microRNAs were reported to increase susceptibility to tumorigenesis; affect prognosis and as promising biomarkers in virus-host interactions. This study was conducted to investigate the role of genetic variants of miR-196a2 (rs 11614913) C>T and miR-499 (rs 3746444) A>G in the development of cirrhosis and HCC in Egyptian HCV infected patients. Genotyping of the candidate SNPs was performed by Real Time PCR in 75 HCV-related HCC patients, 75 cirrhotic patients on top of HCV and 75 healthy controls. There was significant difference in miR-499 (rs3746444) genotypes frequency between the three studied groups as the GG genotype was significantly lower in HCC cases than other groups (P = 0.009) while the combined miR-499 (AA+AG) genotypes were significantly higher in HCC cases than other groups (P = 0.005). Also a significant difference was found in miR-499 genotypes frequency when compared between HCC and cirrhosis groups as the GG genotype was significantly lower in HCC cases than cirrhosis group (P = 0.006) while the combined miR-499 (AA+AG) genotypes were significantly higher in HCC cases than in cirrhosis group (P = 0.003) [OR (95% CI) = 0.131 (0.028-0.601)]. The frequency of the G allele was significantly lower in HCC than other groups (P = 0.024) and significantly lower in HCC than normal group (P = 0.006) [OR (95%CI) = 0.501 (0.304-0.825)]. For miR-196a2 (rs11614913) C>T polymorphisms, no significant association was found with HCC risk. Our study concluded that the G allele of miR-499 is associated with lower risk of HCV related HCC development. No significant association of miR-196a2 (rs 11614913), genotypes or alleles with risk for HCC development, could be detected.     

Single nucleotide polymorphisms of the aromatase gene (CYP19A1), HER2/neu status, and prognosis in breast cancer patients

Purpose Estrogen exposure is involved in both breast cancer susceptibility and the prognosis in patients with breast cancer. Aromatase is involved in the production of estrogens, and altered expression of it might be associated with the prognosis. The aim of this study was to examine the effect of single nucleotide polymorphisms (SNPs) in the aromatase gene, CYP19A1, on the prognosis, and in relation to tumor and patient characteristics in a cohort of breast cancer patients. Patients and methods The cohort analyzed in this study consisted of 1,257 patients with invasive primary breast cancer. Polymorphisms rs10046, rs4646 and rs700519 were genotyped within this group. Results The variant genotypes of rs10046 and rs4646 were associated with a lower percentage of HER2-positive tumors. There was no association of rs700519 and rs4646 with disease-free survival (DFS) or overall survival (OS). The variant genotype of rs10046 was significantly associated with a better 5-year DFS (hazards ratio 0.51; 95% CI, 0.32 to 0.81; P = 0.004) adjusted for age, nodal status, tumor size grading, and hormone receptor status. This effect appeared to be determined in the subgroup of premenopausal patients. Conclusion SNPs rs10046 and rs4646 may influence the HER2 status of breast cancer tumors, and rs10046 genotypes are associated with an altered DFS. Genotypes of aromatase polymorphisms may influence the prognosis for breast cancer patients not only by affecting the extent of estrogen exposure but also through an alteration in tumor characteristics. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

DNA Repair Genes Polymorphisms: Impact on Acute Myeloid Leukemia Patients Outcome

Background: ATM; XRCC6 and LIG4 genes play an important role in repairing the double-strand DNA breaks and maintaining the genome stability. Single nucleotide polymorphisms (SNPs) in these genes could affect these genes expression and function. The aim of this study was to address the effect of SNP of the DNA repairing genes on corresponding  gene expression as well as AML patient’s outcome. Subjects and Methods: This is cross sectional study included 95 newly diagnosed AML patients. For all subjects included in our study SNPs  and expression of ATM (rs189037G>A), XRCC6 (rs2267437C>G) and LIG4 (rs1805388C>T) genes were evaluated by RFLP and real time PCR. Results:The following SNPs in ATM (AA); XRCC6 (GG); and LIG4 (TT) are associated with down regulation of the corresponding genes (P<0.001). The lower expression of ATM and LIG4 genes are associated with shorter OS and DFS. Cox regression multivariate analysis revealed that lower expression of ATM HR : 2.02 (CI: 1.12-3.64; p=0.020. Conclusion: The following SNPs of ATM (AA); XRCC6 (GG); and LIG4 (TT) are associated with down regulation of corresponding genes expression. ATM and XRCC6 lower expression are predictors of OS while ATM is predictor of DFS and could be used for optimizing the AML therapy.     

Polymorphisms of EpCAM gene and prognosis for non‐small‐cell lung cancer in Han Chinese

The epithelial cell adhesion molecule (EpCAM) is overexpressed in a wide variety of human cancers and is associated with patient prognosis, including those with lung cancer. However, the association of single nucleotide polymorphisms (SNPs) in the EpCAM gene with the prognosis for non‐small‐cell lung cancer (NSCLC) patients has never been investigated. We evaluated the association between two SNPs, rs1126497 and rs1421, in the EpCAM gene and clinical outcomes in a Chinese cohort of 506 NSCLC patients. The SNPs were genotyped using the Sequenom iPLEX genotyping system. Multivariate Cox proportional hazards model and Kaplan–Meier curves were used to assess the association of EpCAM gene genotypes with the prognosis of NSCLC. We found that the non‐synonymous SNP rs1126497 was significantly associated with survival. Compared with the CC genotype, the CT+TT genotype was a risk factor for both death (hazard ratio, 1.40; 95% confidence interval [CI], 1.02–1.94; P = 0.040) and recurrence (hazard ratio, 1.34; 95% CI, 1.02–1.77; P = 0.039). However, the SNP rs1421 did not show any significant effect on patient prognosis. Instead, the AG+GG genotype in rs1421 was significantly associated with early T stages (T1/T2) when compared with the AA genotype (odds ratio for late stage = 0.65; 95% CI, 0.44–0.96, P = 0.029). Further stratified analysis showed notable modulating effects of clinical characteristics on the associations between variant genotypes of rs1126497 and NSCLC outcomes. In conclusion, our study indicated that the non‐synonymous SNP rs1126497 may be a potential prognostic marker for NSCLC patients.     

Vascular endothelial growth factor (VEGF) gene polymorphisms may influence the efficacy of thalidomide in multiple myeloma

Vascular endothelial growth factor (VEGF) is a potent proangiogenic factor. Several single nucleotide polymorphisms (SNPs) in the VEGF gene with influence on VEGF expression have been described. In multiple myeloma, VEGF stimulates angiogenesis which is correlated with disease progression and prognosis. In this study, we evaluated the association between genetic variations in the VEGF gene in patients with multiple myeloma and time to treatment failure (TTF) after high-dose melphalan and stem cell support (HDT), overall survival (OS) and efficacy of the anti-angiogenic drug thalidomide. Retrospectively, the SNPs -2,578C>A (rs699947), -460C>T (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) in the VEGF gene were examined in 348 patients with newly diagnosed multiple myeloma initially treated with HDT, where 176 patients were treated with thalidomide at relapse. None of the examined geno- or haplotypes was associated with differences in TTF after initial therapy or OS. A possible relation between the haplotype -2,578A/-460C/+405G (ACG) and effect of thalidomide was seen. Patients with no copies of the haplotype ACG had a longer time to next treatment than patients with one or two copies of the haplotype ACG, median 13.7 months vs. 9.2 months, p=0.007. In conclusion, the haplotype ACG in the VEGF gene may influence the efficacy of thalidomide in multiple myeloma. Further analyses are needed to confirm these findings and get insight into the functional effect of these polymorphisms, so in the future we may be able to select multiple myeloma patients who especially will benefit from treatment with thalidomide.     

PARP1 Gene Polymorphisms and the Prognosis of Esophageal Cancer Patients from Cixian High-Incidence Region in Northern China

Objective: Poly (ADP-ribose) polymerase 1 (PARP1), as a key enzyme in the base excision repair pathway, plays a crucial role in tumorigenesis and progression. This study aimed to assess whether polymorphisms of PARP1 gene could be used as predictive biomarkers for the survival of esophageal squamous cell carcinoma (ESCC) patients from Cixian high-incidence region in northern China. Methods: In 203 ESCC patients with survival information, PARP1 rs1136410 T/C and rs8679 T/C single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) method. All statistical analyses were performed using the SPSS ver. 22.0 software package (SPSS, Chicago, IL, USA). Results: The mean age ± standard deviation of the ESCC patients was 60.4 ± 7.9 years. There was no significant relation of sex, age, smoking status and upper gastrointestinal cancer family history with the survival time of the ESCC patients. The mean survival time of rs1136410 T/T, T/C and C/C genotype carriers were 43.3, 42.3 and 46.6 months, respectively. The rs1136410 was not associated with the survival time of the ESCC patients. For rs8679, the mean survival time of T/T genotype carriers was 43.7 months, which was not significantly different from that of the patients with T/C genotype (42.1 months). Conclusion: In Cixian high-incidence region from northern China, rs1136410 and rs8679 SNPs might not be used to predict survival of ESCC patients. There is a need to explore whether other SNPs of PARP1 gene have an effect on prognosis of ESCC patients.     

Genetic Variation in MicroRNAs and Risk of Oral Squamous Cell Carcinoma in South Indian Population

Background: MicroRNAs (miRNAs) are small non-coding RNA molecules, implicated in several activities like initiation, progression and prognosis of various cancers. Single nucleotide polymorphisms (SNPs) in miRNA genes can lead to alteration in mRNA expression, resulting in diverse functional consequences. The aim of our study was to investigate the association of miR-149C>T and miR-196a2C>T SNPs with susceptibility to development of oral squamous cell carcinoma (OSCC) in South Indian subjects. Materials and Methods: 100 OSCC patients and 102 healthy controls from the general population were recruited for the study. Genetic analysis was performed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) as per a standard protocol. Results: The genotype frequencies in miR-196a2 polymorphism, of TT, CT and CC in the OSCC patients were 69%,10% and 22% respectively while for control group it was 80%, 15% and 5% respectively. The CC genotype of miR196a2 polymorphism was significantly associated with oral squamous cell carcinoma. The genotype frequencies in miR-149 polymorphisms of CC, CT and TT in the oral squamous cell carcinoma (OSCC) patients were 72%, 22% and 6% respectively and for control group 88%, 12% and 0% respectively. CT and TT genotypes of miR149 polymorphism were found to be significantly associated with OSCC (p = 0.05 and 0.07). Conclusions: Our study suggests that miR-196a2C>T and miR-149C>T polymorphisms may play crucial roles in the development of OSCC in South Indian subjects.