Gene polymorphisms involved in folate and methionine metabolism and increased risk of sporadic colorectal adenocarcinoma

This pilot study has compared the polymorphic genotype frequencies of methylenetetrahydrofolate reductase (MTHFR A1298C and C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), and thymidylate synthase (TS 2R/3R) in 113 patients with sporadic colorectal adenocarcinoma (SCA) and 188 healthy blood donors, used as matched controls. The aim was to assess the role of these genotypes in the increased risk of SCA among the southeastern Brazilian population. Carriers of genotype MTRR 66GG, or the combined variants MTHFR 1298AC + CC plus 677CT + TT, or MTHFR 677CT + TT plus MTR 2756AG + GG, or MTHFR 1298AC + CC plus 677CT + TT plus MTR 2756AG + GG, or yet, MTHFR 1298AC + CC plus 677CT + TT plus MTRR 66AG + GG, respectively, showed an increased risk of the order of 1.99-, 3.26-, 2.22-, 10.92-, and 14.88-fold of developing SCA when compared with carriers of the other studied polymorphic genotypes, whether in isolation or in combination. In addition, individuals with the MTHFR 677CT + TT or the MTR 2756AG + GG genotypes had a 2.12- and a 1.42-fold increased risks of SCA onset before 50 years of age. African-Brazilians with the MTRR 66GG genotype had a 1.98-fold increased risk of SCA while individuals with the MTR 2756AG + GG and the MTHFR 677CT + TT genotypes showed a 2.11- and a 1.62-fold increased risk of undifferentiated and advanced tumors at diagnosis, respectively. Carriers of genotype MTHFR 1298AC + CC or MTHFR 1298AC + CC plus MTRR 66AG + GG had a 1.42- and a 3.07-fold increased risk of rectal tumor, respectively. Additionally, carriers of MTHFR 677CT + TT or MTHFR 677CT + TT plus TS 2R/3R + 3R/3R had a 1.55- and a 5.39-fold increased risk for colon tumor, respectively, in comparison with carriers of the wild genotypes. These data suggest that all polymorphisms coding for folate and methionine-dependent enzymes, particularly when present in combination with other polymorphisms, have consistent roles in the increased risk of SCA among the southeastern population of Brazil.     

A non-synonymous polymorphism Thr115Met in the EpCAM gene is associated with an increased risk of breast cancer in Chinese population

As a tumor-associated antigen and a surface marker of breast cancer stem cells (BCSCs), epithelial cell adhesion molecule (EpCAM) plays an important role in not only cell adhesion, morphogenesis, metastases but also carcinogenesis. A non-synonymous C/T polymorphism (rs1126497) in exon3 of EpCAM causes a transition of 115 amino acid from Met to Thr. Another polymorphism (A/G, rs1421) in the 3′UTR causes loss of has-miR-1183 binding. A multiple independent case–control analysis was performed to assess the association between EpCAM genotypes and breast cancer risk. We observed that the variant EpCAM genotype (rs1126497 CT, and TT) was associated with substantially increased risk of breast cancer. Genotyping a total of 1643 individuals with breast cancer and 1818 control subjects in Eastern and Southern Chinese populations showed that rs1126497 CT + TT genotype had an odd ratio of 1.40 (95% confidence interval, 1.16–1.57) for developing breast cancer compared with CC genotype. The allele T increases the risk of breast cancer in a dose-dependent response manner (P _trend < 0.001). Moreover, compared to breast cancer patients carrying the CC genotype, the EpCAM SNP rs1126497 CT or TT carrier was significantly associated with early breast cancer onset (P = 0.0023). However, no significant difference was found in genotype frequencies at the rs1421 A/G site between cases and controls. These findings suggest that M115T polymorphism in EpCAM may be a genetic modifier for developing breast cancer.     

Lack of association of IL-10 gene polymorphisms with prostate cancer: evidence from 11,581 subjects

Published data on the association between interleukin-10 (IL-10) gene polymorphisms and prostate cancer (PCa) are inconclusive. To derive a more precise estimation of the association, we conducted a meta-analysis. Data were collected from the following electronic databases: PubMed, Elsevier Science Direct, Excerpta Medica Database and Chinese Biomedical Literature Database, with the last report up to September 2010. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of association. A total of 13 separate studies including 5503 cases and 6078 controls based on the search criteria were involved in this meta-analysis. Meta-analysis was performed for three IL-10 gene polymorphisms (rs1800896, rs1800871, and rs1800872). We found no association between IL-10 gene rs1800896 polymorphism and PCa in overall population (G versus A: OR = 1.00, 95%CI = 0.91-1.10, P = 0.99; AG + GG versus AA: OR = 1.18, 95%CI = 0.97-1.43, P = 0.10; GG versus AA + AG: OR = 1.04, 95%CI = 0.86-1.26, P = 0.67). In subgroup analysis, similar results were found in Caucasian (G versus A: OR = 0.99, 95%CI = 0.84-1.18, P = 0.92; AG + GG versus AA: OR = 1.32, 95%CI = 0.90-1.94, P = 0.16; GG versus AA + AG: OR = 1.07, 95%CI = 0.89-1.28, P = 0.48), and Asian (G versus A: OR = 0.97, 95%CI = 0.78-1.20, P = 0.78; AG + GG versus AA: OR = 1.07, 95%CI = 0.79-1.45, P = 0.65; GG versus AA + AG: OR = 1.24, 95%CI = 0.38-4.07, P = 0.73) populations. We did not detect an association between IL-10 gene rs1800871 polymorphism and PCa in overall population (T versus C: OR = 0.96, 95%CI = 0.85-1.08, P = 0.51; CT + TT versus CC: OR = 0.94, 95%CI = 0.80-1.11, P = 0.48; TT versus CC + CT: OR = 0.94, 95%CI = 0.81-1.10, P = 0.44). Similar results were found in Asian population (T versus C: OR = 0.85, 95%CI = 0.71-1.09, P = 0.09; CT + TT versus CC: OR = 0.72, 95%CI = 0.52-1.17, P = 0.05; TT versus CC + CT: OR = 0.89, 95%CI = 0.68-1.17, P = 0.39). We found no association between IL-10 gene rs1800872 polymorphism and PCa in overall population (A versus C: OR=1.03, 95%CI = 0.96-1.11, P = 0.41; CA + AA versus CC: OR = 1.04, 95%CI = 0.92-1.17, P = 0.56; AA versus CC + CA: OR = 1.02, 95%CI = 0.85-1.22, P = 0.87). Similar results were found in Caucasian population (A versus C: OR = 1.06, 95%CI = 0.98-1.16, P = 0.16; CA + AA versus CC: OR = 1.07, 95%CI = 0.85-1.35, P = 0.57; AA versus CC + CA: OR = 1.23, 95%CI = 0.92-1.64, P = 0.17). This meta-analysis suggests that there is no association between IL-10 gene rs1800896, rs1800871 and rs1800872 polymorphisms and PCa.     

Genetic Association Analysis Implicates Six MicroRNA-Related SNPs With Increased Risk of Breast Cancer in Australian Caucasian Women

IntroductionBreast cancer (BC), a heterogeneous disease, features microRNA-related single nucleotide polymorphisms (miRSNPs) as underlying factors of BC development, thus providing targets for novel diagnostic and therapeutic strategies. This study investigated miRSNPs in BC susceptibility in Australian Caucasian women.Patients and MethodsThe study population included patients 33 to 80 years of age stratified by molecular subtypes of breast tumors (luminal A, 47.59%), stage (stage I, 36.96%), tumor-type (ductal, 44.95%), grading (intermediate, 35.52%), size (10.1-25 mm, 31.14%), and lymph node (sentinel negative, 38.93%). Sixty-five miRSNPs underwent allelic analysis in two independent case–control cohorts (GU-CCQ-BB, 377 cases and 521 controls; GRC-BC, 267 cases and 201 controls) using a MassARRAY platform. GU-CCQ-BB, GRC-BC, and the combined populations (BC-CA) (644 cases and 722 controls) underwent independent statistical analysis.ResultsIn the GU-CCQ-BB population, miRSNPs TET2-rs7670522, ESR1-rs2046210, FGFR2-rs1219648, MIR210-rs1062099, HIF1A-rs2057482, and CASC16-rs4784227 were found to be associated with increased BC risk (P ≤ .05). Only ESR1-rs2046210 was also significantly associated (P ≤ .05) when replicated in the GRC-BC and BC-CA populations. No significant association was correlated with BC-clinical features (pathological types and ER/PR/HER2 status); however, MIR210-rs1062099 was found to be significantly associated (P ≤ .05) with age (>50 years) in the GU-CCQ-BB cohort.ConclusionThis is the first study to demonstrate the association of MIR210-rs1062099 and TET2-rs7670522 with increased BC risk. Additionally, four previously reported SNPs (ESR1-rs2046210, FGFR2-rs1219648, HIF1A-rs2057482, and CASC16-rs4784227) were confirmed as BC risk variants. Replication and functional studies in larger Caucasian cohorts are necessary to elucidate the role of these miRSNPS in the development of BC.     

BMPR1B Polymorphisms (rs1434536 and rs1970801) are Associated With Breast Cancer Susceptibility in Northwest Chinese Han Females: A Case-Control Study

BackgroundBone morphogenetic proteins receptor type 1B (BMPR1B) was a multifunctional signaling molecule and its abnormal expression associated with poorer prognosis. We aimed to explore the relationship between BMPR1B polymorphisms and breast cancer susceptibility among northwest population.MethodsA total of 450 healthy controls and 434 patients with breast cancers were recruited in this study. Two candidate polymorphisms, rs1434536 and rs1970801 were genotyping using Sequenom MassArray technique. Expression quantitative trait loci analysis in the GTEx portal was adopted to determine the correlation between the rs1434536 and rs1970801 polymorphism and level of BMPR1B expression.ResultsWe found that the T allele of rs1434536 was associated with an increased susceptibility of breast cancer [CT+TT vs. CC: adjusted OR (95% CI) = 1.35(1.02-1.78), P_adjusted = 0.034; CT vs. CC adjusted OR (95% CI) = 1.39(1.03-1.87), P_adjusted = 0.029]. For rs1970801, carrying minor allele T was significantly associated with an increased risk of breast cancer [GT+TT vs. GG: adjusted OR (95% CI) = 1.52(1.14-2.01), P_adjusted = 0.004; GT vs. GG adjusted OR (95% CI) = 1.56(1.15-2.09), P_adjusted = 0.004]. Stratified analyses found statistical significance existing in women under 49 years of age, BMI less than 24 kg/m², and premenopausal women for both rs1434536 and rs1970801. Expression quantitative trait loci analysis in the GTEx portal proved that the minor alleles of rs1434536 T and rs1970801 T was significantly associated with higher expression level of BMPR1B.ConclusionBMPR1B polymorphisms (rs1434536 and rs1970801) may increase susceptibility to breast cancer in Chinese Han women.     

Functional single nucleotide polymorphisms of the RASSF3 gene and susceptibility to squamous cell carcinoma of the head and neck

BackgroundRASSF3 suppresses tumour formation through uncertain mechanisms, but it is an important gene of p53-dependent apoptosis. RASSF3 depletion impairs DNA repair after DNA damage, leading to polyploidy. The authors hypothesised that potential functional single-nucleotide polymorphisms (SNPs) of RASSF3 are associated with risk of squamous cell carcinoma of the head and neck (SCCHN).MethodsThe authors used a functional SNP approach to evaluate the associations between common (minor allele frequency ⩾ 0.05), putative functional variants in RASSF3 and risk of SCCHN. Four selected such functional SNPs (rs6581580 T>G, rs7313765 G>A, rs12311754 G>C and rs1147098 T>C) in RASSF3 were identified and genotyped in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population.ResultsThe authors found that two SNPs were significantly associated with SCCHN risk. Carriers of the variant rs6581580G and rs7313765A alleles were at a reduced SCCHN risk, compared with the corresponding common homozygotes [adjusted odds ratio (OR) = 0.75 and 0.73 and 95% confidence interval (CI) = 0.62–0.91 and 0.60–0.88, respectively, for dominant models; and P_trend = 0.012 and 0.041, respectively, for additive models], particularly for non-oropharyngeal tumours (adjusted OR = 0.68 and 0.60 and 95% CI = 0.53–0.86 and 0.47–0.77, respectively, for dominant models). In the genotype–phenotype correlation analysis of peripheral blood mononuclear cells from 102 cancer-free controls, the rs6581580 GG genotype was associated with significantly increased expression levels of RASSF3 mRNA (P = 0.038), compared with the TT genotype. Additional functional experiments further showed that variant G allele of rs6581580 had a significantly stronger binding affinity to the nuclear protein extracts than the T allele.ConclusionTaken together, these findings indicate that the RASSF3 promoter rs6581580 T>G SNP is potentially functional, modulating susceptibility to SCCHN among non-Hispanic whites. Larger replication studies are needed to confirm our findings.     

Association of genetic polymorphisms of <Emphasis Type="Italic">ER-α</Emphasis> and the estradiol-synthesizing enzyme genes <Emphasis Type="Italic">CYP17</Emphasis> and <Emphasis Type="Italic">CYP19</Emphasis> with breast cancer risk in Chinese women

Estrogen plays a role in breast cancer development, and genetic polymorphisms in estrogen receptor gene ER-α and genes regulating estrogen biosynthesis and metabolisms are associated with the risk of breast cancer in women in western countries. Therefore, we hypothesized that SNPs in ER-α and other estrogen-metabolizing genes contribute to breast cancer risk in Chinese women. In this study, we genotyped polymorphisms in the regulatory regions of ER-α (rs3798577) and other two estrogen-metabolizing enzyme genes CYP17 (rs743572) and CYP19 (rs10046) among 300 breast cancer cases and 390 controls in a Chinese population. Crude and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses to estimate breast cancer risk associated with these polymorphisms. We found that the T allele frequency of ER-α was significantly higher in cases (59.8%) than controls (54.5%) (P = 0.047), but no significant difference was found in the genotype distribution. However, postmenopausal breast cancer risk was associated with the CYP17 TC genotype (aOR = 1.77, 95% CI = 1.11–2.83) compared with the TT genotype. The CYP19 variant TC + TT genotypes were associated with both overall cancer risk (TT + TC vs. TT aOR = 1.73, 95% CI = 1.13–2.65) and premenopausal cancer risk (TT + TC vs. TT aOR = 1.78, 95% CI = 1.03–3.09), particularly for ER +/PR + tumors. Furthermore, there were joint effects between CYP19 T and ER-α T varint genotypes (aOR = 1.67, 95% CI = 1.03–2.69 for CYP19 TC + TT vs. CC among ER-α T variant carriers) and between CYP19 T and CYP17 C variant genotypes (aOR = 1.77, 95% CI = 1.11–2.83 for CYP19 TC + TT vs. CC among CYP17 variant C carriers). This study provides evidence that polymorphisms CYP17 rs743572, CYP19 rs10046 and ER-α rs3798577 are associated with breast cancer risk among Chinese women.     

Association of Genetic Polymorphisms in HSD17B1, HSD17B2 and SHBG Genes with Hepatocellular Carcinoma Risk

Genetic polymorphisms of enzymes involved in estrogen synthesizing/transporting can influence the risk of hormone-dependent diseases. The incidence rate and relative risk for hepatocellular carcinoma (HCC) are higher in men than in women. This study was conducted to explore the relationship of single nucleotide polymorphisms (SNPs) in 17 β-Hydroxysteroid dehydrogenases (HSD17B1 and HSD17B2) and sex hormone-binding globulin (SHBG) genes with the risk of HCC within Chinese Han population. Polymorphisms of HSD17B1 rs676387, HSD17B2 rs8191246 and SHBG rs6259 were genotyped in 253 HCC patients and 438 healthy control subjects using the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Significantly increased HCC risk was found to be associated with T allele of rs676387 and G allele of rs8191246. Increased HCC risks were found in different genetic model (TT genotype in a recessive model, T allele carriers in a dominant model, TT genotype and TG genotype in a codominant model for HSD17B1 rs676387, G allele carriers in a dominant model and AG genotype in a codominant model for HSD17B2 rs8191246, respectively). No association between SHBG rs6259 and HCC risk was observed. The present study provided evidence that HSD17B1 rs676387 and HSD17B2 rs8191246 were association with HCC development. Further studies in diverse ethnic population with larger sample size were recommended to confirm the findings.     

Polymorphisms in the MDM2 gene and risk of malignant bone tumors: a meta-analysis

There are several studies published to assess the associations of murine double minute 2 (MDM2) genetic polymorphisms with risk of malignant bone tumors, but they reported contradictory results and failed to confirm a strong and consistent association. To assess the evidence regarding the associations of MDM2 genetic polymorphisms with the risk of malignant bone tumors, we conducted a meta-analysis of epidemiological studies. The pooled odds ratio (OR) with its 95 % confidence intervals (95 % CI) was used to assess these possible associations. Four studies with a total of 3,958 individuals were finally included the meta-analysis. Meta-analysis of two studies on MDM2 SNP309 polymorphism showed that MDM2 SNP309 polymorphism was associated with an increased risk of malignant bone tumors (G versus T: OR?=?1.72, 95 % CI 1.35–2.20, P?<?0.001; GG versus TT: OR?=?2.64, 95 % CI 1.59–4.39, P?<?0.001; GG/GT versus TT: OR?=?1.87, 95 % CI 1.33–2.62, P?<?0.001; GG versus TT/GT: OR?=?2.20, 95 % CI 1.38–3.51, P?=?0.001). Meta-analysis of those two studies on MDM2 rs1690916 polymorphism showed that MDM2 rs1690916 minor allele A was associated with decreased risk of malignant bone tumors (OR?=?0.60, 95 % CI 0.46–0.77, P?<?0.001). Meta-analyses of available data show that there are significant associations of MDM2 SNP309 polymorphism and MDM2 rs1690916 polymorphism with malignant bone tumors.     

The adiponectin gene single-nucleotide polymorphism rs1501299 is associated with hepatocellular carcinoma risk

Purpose

Increasing lines of evidence have suggested that adiponectin, an adipocyte-derived hormone, plays an important role in the development of hepatocellular carcinoma (HCC). However, the relationship between genetic variants of the adiponectin gene (ADIPOQ) and HCC has not been previously explored. Therefore, we performed a case–control study to examine the association of haplotype-tagging single-nucleotide polymorphisms (SNPs) in ADIPOQ with HCC risk.

Methods

Five haplotype-tagging SNPs of ADIPOQ (rs266729, rs822395, rs822396, rs2241766 and rs1501299) were genotyped in 200 HCC patients and 200 non-HCC controls by PCR amplification and direct sequencing. Logistic regression was used to estimate the risk of HCC associated with each individual SNP and we adjusted for multiple testing by the Bonferroni correction.

Results

Of the five tested SNPs, rs1501299 showed a strong and significant association with HCC risk even after the Bonferroni correction. After adjusting for the serological status of the hepatitis virus B core antibody and for other SNPs, the odds ratios were 4.33 [95 % confidence interval (CI) 2.07–9.05; corrected P < 0.005] and 3.71 (95 % CI 1.84–7.48; corrected P < 0.005) for the GG genotype and GG/GT combined genotype, respectively, versus the TT genotype.

Conclusions

This is the first report, demonstrating an association of ADIPOQ polymorphisms with HCC risk. Our results implicate the ADIPOQ SNP rs1501299 as a susceptibility locus for HCC.     

The Role of Polymorphisms in Glutathione-related Genes in Asbestos-related Diseases

BackgroundThe study investigated the influence of GCLC, GCLM, GSTM1, GSTT1 and GSTP1 polymorphisms, as well as the influence of interactions between polymorphism and interactions between polymorphisms and asbestos exposure, on the risk of developing pleural plaques, asbestosis and malignant mesothelioma (MM).Subjects and methodsThe cross sectional study included 940 asbestos-exposed subjects, among them 390 subjects with pleural plaques, 147 subjects with asbestosis, 225 subjects with MM and 178 subjects with no asbestos-related disease. GCLC rs17883901, GCLM rs41303970, GSTM1 null, GSTT1 null, GSTP1 rs1695 and GSTP1 rs1138272 genotypes were determined using PCR based methods. In statistical analysis, logistic regression was used.ResultsGSTT1 null genotype was associated with the decreased risk for pleural plaques (OR = 0.63; 95% CI = 0.40–0.98; p = 0.026) and asbestosis (OR = 0.51; 95% CI = 0.28–0.93; p = 0.028), but not for MM. A positive association was found between GSTP1 rs1695 AG + GG vs. AA genotypes for MM when compared to pleural plaques (OR = 1.39; 95% CI = 1.00–1.94; p = 0.049). The interactions between different polymorphisms showed no significant influence on the risk of investigated asbestos-related diseases. The interaction between GSTT1 null polymorphism and asbestos exposure decreased the MM risk (OR = 0.17; 95% CI = 0.03–0.85; p = 0.031).ConclusionsOur findings suggest that GSTT1 null genotype may be associated with a decreased risk for pleural plaques and asbestosis, may modify the association between asbestos exposure and MM and may consequently act protectively on MM risk. This study also revealed a protective effect of the interaction between GSTP1 rs1695 polymorphism and asbestos exposure on MM risk.Key words: polymorphisms, glutathione-related genes, asbestos, asbestosis, pleural plaques, malignant mesothelioma     

Rs2686344 and serum squamous cell carcinoma antigen could predict clinical efficacy of neoadjuvant chemotherapy for cervical cancer

ObjectiveTo evaluate the predictive value of a single nucleotide polymorphism (SNP) rs2686344 and squamous cell carcinoma antigen (SCCAg) levels in the clinical efficacy of neoadjuvant chemotherapy (NACT) for cervical cancer.MethodsA total of 92 patients with stage IB2-IIIB carcinoma of the uterine cervix who received NACT treatment were enrolled. The relationship between the genotypes of SNP rs2686344 which is located on CAMKK2 on chromosome 12, SCCAg levels and the response to NACT was analyzed. The relationship between the SNP rs2686344 genotypes, SCCAg levels, the response to NACT and the five-year survival rate was evaluated.ResultsThe effective group accounted for 84.85% in patients with low level (≤3.5 ng/mL) of post-treatment SCCAg (post-SCCAg), while the ineffective group accounted for 15.15%. The post-SCCAg levels and the genotypes of rs2686344 were significantly correlated with NACT response (P = 0.003, and P = 0.006). In patients with CC or CT genotype of SNP rs2686344, effective group accounted for 81.18%, while ineffective group accounted for 18.82%; For patients with TT genotype, effective response group accounted for 28.57%, ineffective group accounted for 71.43%. Post-SCCAg level >3.5 ng/mL and TT genotype of SNP rs2686344 showed as independent risk factors for NACT response in the multivariate analysis (P = 0.002, and P = 0.048). There was no significant difference in 5-year overall survival and 5-year disease-free survival between patients with different levels of post-SCCAg, or among different rs2686344 genotypes.ConclusionThe high level of post-SCCAg (>3.5 ng/mL) and TT genotype of rs2686344 may suggest a higher risk of poor response to NACT.     

Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma

BackgroundProteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, a single nucleotide polymorphism with unknown functional effect, was recently reported to influence response to bortezomib-based therapy in follicular lymphoma.Patients and MethodsWe retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences.ResultsOn univariate analysis, patients carrying the variant G allele showed significantly shorter progression-free survival (PFS) with a pattern suggestive of a gene-dose effect (PFS 26.4, 22.3, and 16.4 months in C/C, C/G, and G/G patients, respectively, P = .002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (hazard ratio [HR] 2.29, P < .001) with a similar trend in C/G carriers (HR 1.33, P = .097) when compared with the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared with that of C/C carriers, despite that PSMB1 expression and proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase- and trypsin-like activity of proteasomes from G/G individuals.ConclusionOur results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes that are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanisms to cope with the abundance of misfolded proteins.     

Genetic variations in the TERT and CLPTM1L gene region and gastrointestinal stromal tumors risk

Recent studies have suggested polymorphisms in the TERT and CLPTM1L region are associated with carcinogenesis of many distinct cancer types, including gastrointestinal cancers. However, the contribution of polymorphisms in the TERT and CLPTM1L gene region to gastrointestinal stromal tumors (GISTs) risk is still unknown. We tested the six tagSNPs on TERT and CLPTM1L region with GIST risk, using a population-based, two-stage, case-control study in 2,000 subjects. Functional validation was conducted to validate our findings of TERT rs2736098 and explore its influence on relative telomere length (RTL) in GIST cells. It showed that variant rs2736098 was significantly associated with increased risk of GIST (per allele OR = 1.29, 95% CI: 1.14–1.47, P = 7.03 × 10⁻⁵). The difference remain significant after Bonferroni correction (P = 7.03 × 10⁻⁵ * 6 = 4.2 × 10⁻⁴). Real-time PCR showed carriers of genotype CC have the longest RTL, following by carriers of genotype CT, while carriers of genotype TT have the shortest RTL in GIST tissues (P < 0.001). Our data provide evidence to implicate TERT rs2736098 polymorphism as a novel susceptibility factor for GIST risk.     

Haplotype-based case–control study of DNA repair gene XRCC3 and hepatocellular carcinoma risk in a Chinese population

Previous studies indicated that the human X-ray repair complementing group 3 gene (XRCC3) plays an important role in hepatocellular carcinoma (HCC) susceptibility. We aimed to investigate the association of XRCC3 genetic polymorphism with HCC risk. This study was conducted in a Chinese Han population consisting of 300 HCC cases and 300 sex- and age-matched cancer-free controls. Three genetic variants (rs861539, rs12432907, and rs861537) were genotyped by the TaqMan® SNP Genotyping Assay. Our findings suggested that the TT genotype and T allele from rs861539 genetic variants were statistically associated with HCC risk. The TT genotype was statistically associated with the increased risk of HCC compared to CC wild genotype (P?<?0.001). And the T allele was more common in the HCC patients than that in the control subjects. (OR?=?1.97, 95 % confidence interval (CI) 1.457?~?2.659, P?<?0.001). Haplotype-based case–control study analysis indicated that TTG haplotype was more frequent in HCC groups than in the control group (odds ratio (OR)?=?1.967, 95 % CI 1.456?~?2.658); however, the CTG haplotype is more common in the control group than that in the HCC group (OR?=?0.550, 95 % CI 0.430?~?0.703; P?<?0.001). Our data indicated that genetic variants of the XRCC3 gene were statistically associated with HCC risk in a Chinese population.     

Differential prognostic impact of different Gleason patterns in grade group 4 in radical prostatectomy specimens

IntroductionThere are questions regarding whether grade group (GG) 4 prostate cancer (PC) is heterogeneous in terms of prognosis. We assessed prognostic differences in PC patients within GG 4 treated with radical prostatectomy (RP).Material and methodsBiochemical recurrence (BCR)-free, cancer-specific, and overall survival were analyzed in 787 PC patients with GG 4 based on RP pathology (Gleason score (GS) 3 + 5: 189, GS 4 + 4: 500, and GS 5 + 3: 98). Logistic regression analysis was performed to assess factors predictive of high-risk surgical pathological features. Cox regression models were used to evaluate potential prognostic factors of survival.ResultsWithin a median follow-up of 86 months, 378 patients (48.0%) experienced BCR and 96 patients (12.2%) died, 42 of whom (5.3%) died of PC. GS 5 + 3 was significantly associated with worse BCR-free and cancer-specific survival, as well as higher positive surgical margin, lymph node metastasis, extraprostatic extension, and non-organ-confined disease rates, than GS 3 + 5 and higher positive surgical margin, lymph node metastasis, extraprostatic extension, and non-organ-confined disease rates than GS 4 + 4 (P < 0.05). GS 4 + 4 was significantly associated with worse BCR-free survival and higher extraprostatic extension, and non-organ-confined disease rates than GS 3 + 5 (P < 0.05). Inclusion of the different Gleason patterns improved the discrimination of a model for prediction of all survival outcomes compared to standard prognosticators.ConclusionsThere is considerable heterogeneity within GG 4 in terms of oncological and surgical pathological outcomes. Primary and secondary Gleason patterns should be considered to stratify high-risk PC patients after RP.