Inhibition of Renin Angiotensin Axis May Be Associated with Reduced Risk of Developing Venous Thromboembolism in Patients with Atherosclerotic Disease

Background

Arterial and venous thrombosis may share common pathophysiology involving the activation of platelets and inflammatory mediators. A growing body of evidence suggests prothrombotic effect of renin angiotensin system (RAS) including vascular inflammation and platelet activation. We hypothesized that the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) plays a role in protecting against venous thromboembolism (VTE) in patients atherosclerosis.

Methods

We conducted a retrospective study, reviewing 1,100 consecutive patients admitted to a teaching hospital with a diagnosis of either myocardial infarction or ischemic stroke from 2005 to 2010. Patients who had been treated with anticoagulation therapy before or after the first visit were excluded. The occurrence of VTE during the follow up period, risk factors for VTE on admission, and the use of ACEIs or ARBs during the follow up period were recorded.

Results

The mean age of the entire study population was 68.1 years. 52.0% of the patients were female and 76.5% were African American. 67.3% were on RAS inhibitorsThe overall incidence of VTE was 9.7% (n = 107). Among the RAS inhibitor users, the incidence of VTE events was 9.0% (54/603) for the ACEI only users, 7.1% (8/113) for the ARB only users, and 0% (0/24) for the patients taking combination of ACEI and ARB. Among patients on RAS inhibitors, 8.4% (62/740) developed a VTE, compared with 12.5% (45/360) in the nonuser group [HR (hazard ratio), 0.58; 95% CI (confidence interval), 0.39–0.84; P<0.01]. Even after controlling for factors related to VTE (smoking, history of cancer, and immobilization, hormone use) and diabetes, the use of RAS inhibitors was still associated with a significantly lower risk of developing VTE (AHR, 0.59; 95% CI, 0.40–0.88; P = 0.01).

Conclusions

The use of RAS inhibitors appears to be associated with a reduction in the risk of VTE.     

Colon Cancer-Specific Antigen-2 May Be Used as a Detecting and Prognostic Marker in Colorectal Cancer: A Preliminary Observation

Background

A specific and sensitive serum marker for colorectal cancer (CRC) detection and surveillance is central to effective treatment. It was preliminarily reported that some nuclear matrix proteins may be served as a specific blood based marker for colon cancer. The objective of this study is to evaluate the value of serum CCSA-2 detection in diagnosis, prognostic estimation and surveillance for CRC.

Method

Serum CCSA-2 protein was measured in 181 various patient populations and 20 healthy donors before surgery. For 106 CRC patients, it was also measured on day 7 after surgery. Among them, 49 CRC patients'' CCSA-2 protein were measured during the follow-up period according to NCCN Guideline.

Results

The serum CCSA-2 concentration in CRC patients was significantly higher than which in other patients and healthy individuals. Serum CCSA-2, at the cut-off point of 64.10 ng/mL, had a sensitivity of 98.10% and a specificity of 97.90% in separating CRC populations from all other individuals. The CCSA-2 assay was significantly more sensitive than CEA and CA19-9 assay in CRC detection. After surgery, the serum CCSA-2 level of CRC patients declined significantly, but it rebounded to a high level when recurrences occurred. The pre-operative serum CCSA-2 level in patients who had a relapse within the follow-up period was significantly higher than which in patients without relapse.

Conclusions

Serum CCSA-2 not only may be a potential biomarker using in screening and surveillance of CRC, but also may be an independent prognostic marker for CRC patients. Further clinical trials need to be performed in a larger population of patients to ulteriorly confirm these results.     

粪便DNA突变检测在快速筛选大肠癌中的应用

大肠癌是发病率和死亡率都很高的常见疾病, 对高危人群进行大规模的普查筛选, 可以降低大肠癌的发生率和死亡率。粪便DNA突变检测是新近发展的可用作大肠癌普查的技术, 与常规结肠镜检测和大便隐血实验相比, 具有特异性高、灵敏度高和易于被患者接受等优点。文章阐述了粪便DNA突变检测的相关基因、肿瘤特异性DNA提取方法和检测方法等, 并对其在快速筛选大肠癌中的应用进行了展望。大肠癌是发病率和死亡率都很高的常见疾病, 对高危人群进行大规模的普查筛选, 可以降低大肠癌的发生率和死亡率。粪便DNA突变检测是新近发展的可用作大肠癌普查的技术, 与常规结肠镜检测和大便隐血实验相比, 具有特异性高、灵敏度高和易于被患者接受等优点。文章阐述了粪便DNA突变检测的相关基因、肿瘤特异性DNA提取方法和检测方法等, 并对其在快速筛选大肠癌中的应用进行了展望。     

Genetic Polymorphisms of the CASP8 Gene Promoter May Not Be Associated with Colorectal Cancer in Han Chinese from Southwest China

Purpose

Caspase 8 (CASP8) plays a critical role in the apoptotic pathway and aberrant regulation of this pathway causes many diseases including cancers. Genetic variants rs3834129 (CTTACT/−) and rs3769821 (T/C) in the promoter region of the CASP8 gene were documented to be associated with multiple solid cancers and non-Hodgkin’s lymphoma (NHL), respectively, despite of some controversies. We aimed to discern potential association of these two variants and rs113686495 (CTGTCATT/−), as well as CASP8 mRNA and protein expression levels with colorectal cancer (CRC) in Han Chinese.

Methods

We genotyped CASP8 genetic variants in 305 CRC patients and 342 healthy individuals from Kunming, Southwest China. Expression levels of CASP8 mRNA and protein were quantified in paired cancerous and paracancerous normal tissues by using real-time quantitative PCR and western blot, respectively. We compared the frequencies of alleles, genotypes, and haplotypes between the cases and controls. Correlation of CASP8 mRNA and protein expression levels in paired cancerous and paracancerous normal tissues from patients with different genotypes and clinical expression were also evaluated.

Results

There was no association of the CASP8 genetic variants with CRC in our case-control study. The CASP8 gene mRNA expression levels in cancerous and paracancerous normal tissues were similar and there was no significant difference between subjects with different genotypes and clinical features. However, we found that CASP8 protein level was significantly lower in cancerous tissues than in paired paracancerous normal tissues.

Conclusions

Our results suggest that the three CASP8 genetic variants may not be associated with CRC risk in Han Chinese from southwest China. Aberrant CASP8 protein expression may play a role in the pathogenesis of CRC.     

A Retrospective Observational Study of the Relationship between Single Nucleotide Polymorphisms Associated with the Risk of Developing Colorectal Cancer and Survival

BackgroundThere is variability in clinical outcome for patients with apparently the same stage colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) mapping to chromosomes 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and Xp22 have robustly been shown to be associated with the risk of developing CRC. Since germline variation can also influence patient outcome the relationship between these SNPs and patient survivorship from CRC was examined.MethodsAll enrolled into the National Study of Colorectal Cancer Genetics (NSCCG) were genotyped for 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and xp22 SNPs. Linking this information to the National Cancer Data Repository allowed patient genotype to be related to survival.ResultsThe linked dataset consisted of 4,327 individuals. 14q22.22 genotype defined by the SNP rs4444235 showed a significant association with overall survival. Specifically, the C allele was associated with poorer observed survival (per allele hazard ratio 1.13, 95% confidence interval 1.05–1.22, P = 0.0015).ConclusionThe CRC susceptibility SNP rs4444235 also appears to exert an influence in modulating patient survival and warrants further evaluation as a potential prognostic marker.     

DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10⁻³) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10⁻³). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.     

Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.     

Risk of Advanced Neoplasia in First-Degree Relatives with Colorectal Cancer: A Large Multicenter Cross-Sectional Study

BackgroundFirst-degree relatives (FDR) of patients with colorectal cancer have a higher risk of developing colorectal cancer than the general population. For this reason, screening guidelines recommend colonoscopy every 5 or 10 y, starting at the age of 40, depending on whether colorectal cancer in the index-case is diagnosed at <60 or ≥60 y, respectively. However, studies on the risk of neoplastic lesions are inconclusive. The aim of this study was to determine the risk of advanced neoplasia (three or more non-advanced adenomas, advanced adenoma, or invasive cancer) in FDR of patients with colorectal cancer compared to average-risk individuals (i.e., asymptomatic adults 50 to 69 y of age with no family history of colorectal cancer).ConclusionsIndividuals having two FDR with colorectal cancer showed an increased risk of advanced neoplasia compared to those with average-risk for colorectal cancer. Men had over 2-fold higher risk of advanced neoplasia than women, independent of family history. These data suggest that screening colonoscopy guidelines should be revised in the familial-risk population.     

营养风险筛查在结直肠癌快速康复外科治疗中的作用

目的:探讨营养风险筛查在结直肠癌快速康复外科治疗中的作用,提高结直肠癌患者术后的营养状况和胃肠道免疫功能,促进胃肠道功能的恢复。方法:收集60例结直肠癌择期手术患者,并将其随机分为快速康复组(FTS)和传统治疗组,分别用快速康复措施和传统方法进行围手术期的处理,其中引入术前营养风险筛查和预防性营养干预,比较两组患者的术后营养状况与胃肠道免疫功能及术后肛门排气时间、术后住院日、住院总费用的差异。结果:与传统组相比,FTS组术后血清白蛋白(ABL)水平明显升高(P0.01),C反应蛋白(CRP)水平明显降低(P0.01),术后胃肠功能恢复更早,术后住院日更短(P0.05),但两组的住院总费用和并发症的发生率比较无明显差异(P0.05)。结论:术前营养风险筛查并营养干有助于结直肠癌的快速康复外科治疗。     

Concomitant Tumor Expression of EGFR and TATI/SPINK1 Associates with Better Prognosis in Colorectal Cancer

Background

Epidermal growth factor receptor (EGFR) activation plays a role in colorectal cancer (CRC) carcinogenesis, and anti-EGFR drugs are used in treatment of advanced CRC. One of the EGFR ligands is tumor-associated trypsinogen inhibitor TATI, also called serine protease inhibitor Kazal type1 (SPINK 1), which we recently showed to be an independent prognostic marker in CRC.

Methods

We studied the prognostic value of immunohistochemical expression of EGFR and concomitant expression of EGFR and TATI/SPINK1 in a series of 619 colorectal cancer patients.

Results

Of the samples, 92% were positive for EGFR. EGFR+/TATI+ was seen in 62.8%, EGFR+/TATI− in 29.5%, EGFR−/TATI+ in 4.9%, and EGFR−/TATI− in 2.7% of patients. EGFR expression correlated with WHO grade (p = 0.040). In univariate analysis, EGFR expression correlated with favourable survival (p = 0.006). EGFR+/TATI+ patients showed better survival than did those with other combinations (p<0.001). In multivariate analysis, EGFR+/TATI+ was an independent prognostic factor of favourable prognosis (p<0.001).

Conclusion

Concomitant positivity of EGFR and TATI/SPINK1 predicts favourable prognosis in CRC.     

Risk of Intestinal Parasitic Infections in People with Different Exposures to Wastewater and Fecal Sludge in Kampala,Uganda: A Cross-Sectional Study

BackgroundThere are health risks associated with wastewater and fecal sludge management and use, but little is known about the magnitude, particularly in rapidly growing urban settings of low- and middle-income countries. We assessed the point-prevalence and risk factors of intestinal parasite infections in people with different exposures to wastewater and fecal sludge in Kampala, Uganda.MethodologyA cross-sectional survey was carried out in September and October 2013, enrolling 915 adults from five distinct population groups: workers maintaining wastewater facilities; workers managing fecal sludge; urban farmers; slum dwellers at risk of flooding; and slum dwellers without risk of flooding. Stool samples were subjected to the Kato-Katz method and a formalin-ether concentration technique for the diagnosis of helminth and intestinal protozoa infections. A questionnaire was administered to determine self-reported signs and symptoms, and risk factors for intestinal parasite infections. Univariate and multivariate analyses, adjusted for sex, age, education, socioeconomic status, water, sanitation, and hygiene behaviors, were conducted to estimate the risk of infection with intestinal parasites and self-reported health outcomes, stratified by population group.Conclusions/SignificanceUrban farmers are particularly vulnerable to infections with soil-transmitted helminths, S. mansoni, and intestinal protozoa. Hence, our findings call for public health protection measures for urban farmers and marginalized communities, going hand-in-hand with integrated sanitation safety planning at city level.     

A Distinct Class of Antibodies May Be an Indicator of Gray Matter Autoimmunity in Early and Established Relapsing Remitting Multiple Sclerosis Patients

We have previously identified a distinct class of antibodies expressed by B cells in the cerebrospinal fluid (CSF) of early and established relapsing remitting multiple sclerosis (RRMS) patients that is not observed in healthy donors. These antibodies contain a unique pattern of mutations in six codons along V_H4 antibody genes that we termed the antibody gene signature (AGS). In fact, patients who have such B cells in their CSF are identified as either having RRMS or developing RRMS in the future. As mutations in antibody genes increase antibody affinity for particular antigens, the goal for this study was to investigate whether AGS⁺ antibodies bind to brain tissue antigens. Single B cells were isolated from the CSF of 10 patients with early or established RRMS. We chose 32 of these B cells that expressed antibodies enriched for the AGS for further study. We generated monoclonal full-length recombinant human antibodies (rhAbs) and used both immunological assays and immunohistochemistry to investigate the capacity of these AGS⁺ rhAbs to bind brain tissue antigens. AGS⁺ rhAbs did not recognize myelin tracts in the corpus callosum. Instead, AGS⁺ rhAbs recognized neuronal nuclei and/or astrocytes, which are prevalent in the cortical gray matter. This pattern was unique to the AGS⁺ antibodies from early and established RRMS patients, as AGS⁺ antibodies from an early neuromyelitis optica patient did not display the same reactivity. Prevalence of CSF-derived B cells expressing AGS⁺ antibodies that bind to these cell types may be an indicator of gray matter-directed autoimmunity in early and established RRMS patients.     

Comparison of Genetic and Epigenetic Alterations of Primary Tumors and Matched Plasma Samples in Patients with Colorectal Cancer

BackgroundAlthough recent advances in circulating DNA analysis allow the prediction of tumor genomes by noninvasive means, some challenges remain, which limit the widespread introduction of cfDNA in cancer diagnostics. We analyzed the status of the two best characterized colorectal cancer (CRC) genetic and epigenetic alterations in a cohort of CRC patients, and then compared the degree to which the two patterns move from tissue to plasma in order to improve our understanding of biology modulating the concordance between tissues and plasma methylation and mutation profiles.MethodsPlasma and tumor tissues were collected from 85 patients (69±14 years, 56 males). KRAS and SEPT9 status was assessed by allele refractory mutation system quantitative PCR and quantitative methylation-specific PCR, respectively. Six of the most common point mutations at codon 12 and 13 were investigated for KRAS analysis.ResultsKRAS mutations and SEPT9 promoter methylation were present in 34% (29/85) and in 82% (70/85) of primary tumor tissue samples. Both genetic and epigenetic analyses of cfDNA revealed a high overall concordance and specificity compared with tumor-tissue analyses. Patients presenting with both genetic and epigenetic alterations in tissue specimens (31.8%, 27/85) were considered for further analyses. The median methylation rates in tumour tissues and plasma samples were 64.5% (12.2–99.8%) and 14.5% (0–45.5%), respectively. The median KRAS mutation load (for matched mutations) was 33.6% (1.8–86.3%) in tissues and 2.9% (0–17.3) in plasma samples. The plasma/tissue (p/t) ratio of SEPT9 methylation rate was significantly higher than the p/t ratio of KRAS mutation load, especially in early stage cancers (p=0.0108).ConclusionThe results of this study show a discrepant rate of epigenetic vs. genetic alterations moving from tissue to plasma. Many factors could affect mutation cfDNA analysis, including both presence of tumor clonal heterogeneity and strict compartmentalization of KRAS mutation profile. The present study highlights the importance of considering the nature of the alteration when analyzing tumor-derived cfDNA.     

The Performance of Three-Sample Qualitative Immunochemical Fecal Test to Detect Colorectal Adenoma and Cancer in Gastrointestinal Outpatients: An Observational Study

Background

Repeated qualitative fecal immunochemical test (qlFIT) is a clinical strategy widely used to detect lower gastrointestinal lesions, but its diagnostic power has not been assessed in opportunistic screening for colorectal neoplasia.

Objective

This study aimed to determine the performance of three-sample qlFIT in screening for colorectal cancer and its precursors in high-risk participants.

Methods

513 gastrointestinal outpatients yielded three qlFITs before a standard colonoscopy. We evaluated the diagnostic value of one, two, and three positive qlFITs serving as the positivity threshold. The risk factors of colorectal neoplasia to yield positive qlFITs were also determined.

Results

52 patients were diagnosed with colorectal cancer and 70 with advanced adenomatous polyp. For colorectal cancer, the sensitivity and specificity of one positive qlFIT were 90.4% and 53.8%, of two were 80.8% and 75.1%, and of three were 53.9% and 88.5%, respectively. For advanced adenomatous polyp, the sensitivity and specificity of one positive qlFIT were 81.4% and 54.2%, of two were 50.0% and 72.5%, and of three were 28.6% and 86.2%. Left-sided location (OR 2.50, 95%CI 1.26–4.95) and advanced histology of tumors (OR 3.08, 95%CI 1.58–6.01) were independently associated with positive qlFITs.

Conclusions

Three-sample qlFIT is a reasonably good method to detect colorectal neoplasia in high-risk population. Tumors in the left side or with advanced pathological features are more likely to produce positive qlFITs.     

Risk Factors for Colorectal Cancer in Patients with Multiple Serrated Polyps: A Cross-Sectional Case Series from Genetics Clinics

Background

Patients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps.

Methods and Findings

We identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P = 0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes.

Conclusion

A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.     

Better Long-Term Survival in Young Patients with Non-Metastatic Colorectal Cancer after Surgery,an Analysis of 69,835 Patients in SEER Database

Objective

To compare the long-term survival of colorectal cancer (CRC) in young patients with elderly ones.

Methods

Using Surveillance, Epidemiology, and End Results (SEER) population-based data, we identified 69,835 patients with non-metastatic colorectal cancer diagnosed between January 1, 1988 and December 31, 2003 treated with surgery. Patients were divided into young (40 years and under) and elderly groups (over 40 years of age). Five-year cancer specific survival data were obtained. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors.

Results

Young patients showed significantly higher pathological grading (p<0.001), more cases of mucinous and signet-ring histological type (p<0.001), later AJCC stage (p<0.001), more lymph nodes (≥12 nodes) dissected (p<0.001) and higher metastatic lymph node ratio (p<0.001). The 5-year colorectal cancer specific survival rates were 78.6% in young group and 75.3% in elderly group, which had significant difference in both univariate and multivariate analysis (P<0.001). Further analysis showed this significant difference only existed in stage II and III patients.

Conclusions

Compared with elderly patients, young patients with colorectal cancer treated with surgery appear to have unique characteristics and a higher cancer specific survival rate although they presented with higher proportions of unfavorable biological behavior as well as advanced stage disease.     

Polymorphisms of Glucose-Regulated Protein 78 and Risk of Colorectal Cancer: A Case-Control Study in Southwest China

Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone, up-regulation serves as an efficient mechanism to promote malignant transformation of colorectal cancer (CRC) and protect CRC cells against apoptosis. Recently, the analysis of GRP78 polymorphisms has already determined that GRP78 rs391957 polymorphism could predict clinical outcome in CRC patients. Thus, we tested whether GRP78 polymorphisms are related to the risk of CRC. In this study, we detected two GRP78 polymorphisms (rs391957 (C>T) and rs430397 (G>A)) in 414 CRC cases and 502 hospital-based cancer-free healthy controls in Southwest China using a polymerase chain reaction–restriction fragment length polymorphism technique. Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of CRC (odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.06–1.83 for CT genotype and OR = 2.10, 95% CI = 1.06–4.14 for TT genotype, respectively). In CRC cases, the variant T allele was significantly associated with tumor invasion stage (P = 0.030), but not with status of lymph nodes metastasis (P = 0.052). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of CRC (OR = 1.63, 95% CI = 1.23–2.15 for GA genotype and OR = 2.92, 95% CI = 1.23–6.94 for AA genotype, respectively). The rs430397 polymorphism was not associated with the clinicopathological characteristics of CRC. These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as markers to predict the risk of CRC.     

The Associations between RNA Splicing Complex Gene SF3A1 Polymorphisms and Colorectal Cancer Risk in a Chinese Population

Background

Aberrant alternative splicing included alterations in components of the mRNA splicing machinery often occurred in colon cancer. However, the role of SF3A1, one key component of the mRNA splicing machinery, on colorectal cancer (CRC) risk was still not elucidated.

Method and Findings

We performed a hospital-based case-control study containing 801 CRC patients and 817 cancer-free controls to examine the association between SF3A1 polymorphisms and CRC risk in a Chinese population. Four candidate SNPs (rs10376, rs5753073, rs2839998 and rs2074733) were selected based on bioinformatics analysis and previous findings. The results showed no significant associations between these SNPs and CRC risk (P > 0.05). Besides, the stratified analysis based on the smoking and alcohol use status obtained no statistically significant results.

Conclusion

Our study was the first one to investigate the association between SF3A1 polymorphisms and CRC risk. The results suggested these four SNPs in SF3A1 were not associated with CRC risk in a Chinese population, however, further more studies are needed to confirm our findings.     

The Joint Effects of Lifestyle Factors and Comorbidities on the Risk of Colorectal Cancer: A Large Chinese Retrospective Case-Control Study

Background

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality. In previous epidemiologic studies, the respective correlation between lifestyle factors and comorbidity and CRC has been extensively studied. However, little is known about their joint effects on CRC.

Methods

We conducted a retrospective case-control study of 1,144 diagnosed CRC patients and 60,549 community controls. A structured questionnaire was administered to the participants about their socio-demographic factors, anthropometric measures, comorbidity history and lifestyle factors. Logistic regression model was used to calculate the odds ratio (ORs) and 95% confidence intervals (95%CIs) for each factor. According to the results from logistic regression model, we further developed healthy lifestyle index (HLI) and comorbidity history index (CHI) to investigate their independent and joint effects on CRC risk.

Results

Four lifestyle factors (including physical activities, sleep, red meat and vegetable consumption) and four types of comorbidity (including diabetes, hyperlipidemia, history of inflammatory bowel disease and polyps) were found to be independently associated with the risk of CRC in multivariant logistic regression model. Intriguingly, their combined pattern- HLI and CHI demonstrated significant correlation with CRC risk independently (OR_HLI: 3.91, 95%CI: 3.13–4.88; OR_CHI: 2.49, 95%CI: 2.11–2.93) and jointly (OR: 10.33, 95%CI: 6.59–16.18).

Conclusions

There are synergistic effects of lifestyle factors and comorbidity on the risk of colorectal cancer in the Chinese population.