Lack of significant associations between single nucleotide polymorphisms in LPAL2-LPA genetic region and all cancer incidence and mortality in Japanese population: The Japan public health center-based prospective study

BackgroundHigh lipoprotein (a) level is an established cardiovascular risk, but its association with non-cardiovascular diseases, especially cancer, is controversial. Serum lipoprotein (a) levels vary widely by genetic backgrounds and are largely determined by the genetic variations of apolipoprotein (a) gene, LPA. In this study, we investigate the association between SNPs in LPA region and cancer incidence and mortality in Japanese.MethodsA genetic cohort study was conducted utilizing the data from 9923 participants in the Japan Public Health Center-based Prospective Study (JPHC Study). Twenty-five SNPs in the LPAL2-LPA region were selected from the genome-wide genotyped data. Cox regression analysis adjusted for the covariates and competing risks of death from other causes, were used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of overall and site-specific cancer incidence and mortality, for each SNP.ResultsNo significant association was found between SNPs in the LPAL2-LPA region and cancer incidence or mortality (overall/site-specific cancer). In men, however, HRs for stomach cancer incidence of 18SNPs were estimated higher than 1.5 (e.g., 2.15 for rs13202636, model free, 95%CI: 1.28–3.62) and those for stomach cancer mortality of 2SNPs (rs9365171, rs1367211) were estimated 2.13 (recessive, 95%CI:1.04–4.37) and 1.61 (additive, 95%CI: 1.00–2.59). Additionally, the minor allele for SNP rs3798220 showed increased death risk from colorectal cancer (CRC) in men (HR: 3.29, 95% CI:1.59 – 6.81) and decreased CRC incidence risk in women (HR: 0.46, 95%CI: 0.22–0.94). Minor allele carrier of any of 4SNPs could have risk of prostate cancer incidence (e.g., rs9365171 dominant, HR: 1.71, 95%CI: 1.06–2.77).ConclusionsNone of the 25 SNPs in the LPAL2-LPA region was found to be significantly associated with cancer incidence or mortality. Considering the possible association between SNPs in LPAL2-LPA region and colorectal, prostate and stomach cancer incidence or mortality, further analysis using different cohorts is warranted.     

The relation between resting heart rate and cancer incidence,cancer mortality and all-cause mortality in patients with manifest vascular disease

BackgroundPrevious studies suggest that elevated resting heart rate (RHR) is related to an increased risk of cancer mortality. The aim of this study was to evaluate the relation between RHR and cancer incidence and mortality in patients with vascular disease.MethodsPatients with manifest vascular disease (n = 6007) were prospectively followed-up for cancer incidence and mortality. At baseline, RHR was obtained from an electrocardiogram. The relation between RHR and cancer incidence, cancer mortality and total mortality was assessed using competing risks models.ResultsDuring a median follow-up of 6.0 years (interquartile range: 3.1–9.3) 491 patients (8%) were diagnosed with cancer and 907 (15%) patients died, 248 (27%) died from cancer. After adjustment for potential confounders, the hazard ratio (HR) for incident cancer per 10 beats/min increase in RHR was 1.00 (95% confidence interval [CI]: 0.93–1.07). There was a trend toward an increased risk of colorectal cancer in patients with higher RHR (HR 1.15, 95% CI 0.97–1.36). The risk of all-cause mortality was increased in patients in the highest quartile of RHR compared to the lowest quartile (HR 1.86, 95% CI 1.53–2.27), but no effect of RHR on cancer mortality was observed (HR 1.01, 95% CI 0.70–1.46).ConclusionsIn patients with manifest vascular disease, elevated RHR was related to a higher risk of premature all-cause mortality, but this was not due to increased cancer mortality. RHR was not related to risk of overall cancer incidence, although a relation between elevated RHR and incident colorectal cancer risk could not be ruled out.     

Effects of polymorphisms in translesion DNA synthesis genes on lung cancer risk and prognosis in Chinese men

PurposeTranslesion DNA synthesis (TLS) plays an important role in promoting replication through DNA lesions. Genetic polymorphisms in TLS genes may have potential roles in lung cancer development in humans.MethodsWe evaluated the association between genetic variants in six TLS genes and the risk and survival of lung cancer in a case–control study in China. Included in the study are 224 lung cancer patients and 448 healthy controls.ResultsCarriers of the G allele of POLκ rs5744724 had significantly reduced risk of lung cancer (odds ratio (OR) = 0.62, 95% confidence interval (CI): 0.44–0.89), comparing with those carrying the C allele, and the AA genotype of PCNA rs25406 was also associated with significantly decreased cancer risk compared with the major homozygote alleles (OR = 0.47, 95% CI: 0.25–0.86). Haplotype analysis showed that subjects with the POLκ C-G (rs5744533–rs5744724) haplotype had decreased risk of lung cancer (OR = 0.69, 95% CI: 0.49–0.98), comparing with those carrying the C-C haplotype. Besides, the heterozygote of REV1 rs3087386 and rs3792136 were independent prognostic factors for lung cancer survival with hazard radio (HR) 1.54 (95% CI: 1.12–2.12) and 1.44 (95% CI: 1.06–1.97) respectively.ConclusionsOur findings suggested that genetic variants in POLκ and PCNA genes may play roles in the susceptibility of lung cancer, and REV1 gene may have roles in lung cancer survival in Chinese men.     

Diabetes,metformin use,and colorectal cancer survival in postmenopausal women

Background: Observational studies have associated metformin use with lower colorectal cancer (CRC) incidence but few studies have examined metformin's influence on CRC survival. We examined the relationships among metformin use, diabetes, and survival in postmenopausal women with CRC in the Women's Health Initiative (WHI) clinical trials and observational study. Methods: 2066 postmenopausal women with CRC were followed for a median of 4.1 years, with 589 deaths after CRC diagnosis from all causes and 414 deaths directly attributed to CRC. CRC-specific survival was compared among women with diabetes with metformin use (n = 84); women with diabetes with no metformin use (n = 128); and women without diabetes (n = 1854). Cox proportional hazard models were used to estimate associations among metformin use, diabetes and survival after CRC. Strategies to adjust for potential confounders included: multivariate adjustment with known predictors of colorectal cancer survival and construction of a propensity score for the likelihood of receiving metformin, with model stratification by propensity score quintile. Results: After adjusting for age and stage, CRC specific survival in women with diabetes with metformin use was not significantly different compared to that in women with diabetes with no metformin use (HR 0.75; 95% CI 0.40–1.38, p = 0.67) and to women without diabetes (HR 1.00; 95% CI 0.61–1.66, p = 0.99). Following propensity score adjustment, the HR for CRC-specific survival in women with diabetes with metformin use compared to non-users was 0.78 (95% CI 0.38–1.55, p = 0.47) and for overall survival was 0.86 (95% CI 0.49–1.52; p = 0.60). Conclusions: In postmenopausal women with CRC and DM, no statistically significant difference was seen in CRC specific survival in those who used metformin compared to non-users. Analyses in larger populations of colorectal cancer patients are warranted.     

A missense variant in PTPN12 associated with the risk of colorectal cancer by modifying Ras/MEK/ERK signaling

BackgroundThe classical protein tyrosine phosphatases (PTPs) have been widely reported to be associated with various human malignancies including colorectal cancer (CRC). However, there are few comprehensive analyses of the association between the classical PTP genes and CRC risk.MethodsFirst, a bioinformatics analysis was performed to identify missense variants within the classical PTP gene family. Second, exome-wide association data and an independent population study were conducted to evaluate effects of candidate variants on CRC risk. Finally, functional assays based on signaling pathways were applied to uncover the potential pathogenic mechanism.ResultsWe identified that PTPN12 rs3750050 G allele presented a 19% increase the risk of CRC, with an OR of 1.19 (95% CI = 1.09–1.30, P = 1.015×10⁻⁴) under an additive model in the combined analysis. Furthermore, biochemical assays illustrated that rs3750050 could impair the inhibitory effect of PTPN12 on Ras/MEK/ERK signaling by impeding SHC dephosphorylation, increase the expression of cyclin D1 and ultimately lead to aberrant cell proliferation, thus contributing to CRC pathogenesis.ConclusionOur study highlights that PTPN12 rs3750050 could increase CRC risk by modifying Ras/MEK/ERK signaling. This work provides a novel insight into the roles of genetic variants within PTP genes in the pathogenesis of CRC.     

No association between garlic intake and risk of colorectal cancer

BackgroundAlthough experimental studies suggested beneficial role of garlic intake on colorectal carcinogenesis, limited prospective cohort studies have evaluated garlic intake in relation to colorectal cancer (CRC) incidence.MethodsWe followed 76,208 women in the Nurses’ Health Study and 45,592 men in the Health Professionals Follow-up Study for up to 24 years and examined garlic intake and garlic supplement use in relation to CRC risk. Information on garlic intake and supplement use was assessed using a validated food frequency questionnaire and a Cox proportional hazard regression model was used to estimate the multivariable hazard ratio (MV-HR) and 95% confidence intervals (95% CIs).ResultsWe documented 2368 (1339 women and 1029 men) incident CRC cases and found no association between garlic intake and CRC risk; the MV-HRs (95% CIs) associated with garlic (1 clove or 4 shakes per serving) intake ≥1/day compared with <1/month were 1.21 (0.94–1.57; p-trend = 0.14) for women and 1.00 (0.71–1.42; p-trend = 0.89) for men. The MV-HRs (95% CIs) of CRC for garlic supplement use, which was used in 6% of the participants in each study, were 0.72 (0.48–1.07) for women and 1.22 (0.83–1.78) for men.ConclusionOur prospective data do not support an important role of garlic intake or garlic supplement use in colorectal carcinogenesis.     

Association between Body Mass Index and Prognosis of Colorectal Cancer: A Meta-Analysis of Prospective Cohort Studies

Studies have reported conflicting results on the association between body mass index (BMI) and prognosis of colorectal cancer. Therefore, we have conducted a meta-analysis of prospective studies, which examined the association of pre- and post-diagnostic BMI with colorectal cancer-specific mortality and all-cause mortality in patients with colorectal cancer. We searched Medline and EMBASE database published between 1970 and September 2014. A total of 508 articles were identified, of which 16 prospective cohort studies were included for the current meta-analysis. The analysis included 58,917 patients who were followed up over a period ranging from 4.9 to 20 years (median: 9.9 years). We found that being underweight before cancer diagnosis was associated with increased all-cause mortality (Relative risk [RR]: 1.63, 95% CI: 1.18–2.23, p < 0.01) and being obese (BMI ≥ 30 kg/m²) before cancer diagnosis was associated with increased colorectal cancer-specific mortality (RR: 1.22, 95% CI: 1.003–1.35, p < 0.01) and all-cause mortality (RR: 1.25, 95% CI: 1.14–1.36, p < 0.01). On the other hand, being underweight (RR: 1.33, 95% CI: 1.20–1.47, p < 0.01), obese (RR: 1.08, 95% CI: 1.03–1.3, p < 0.01), and class II/III obese (BMI ≥ 35 kg/m²; RR: 1.13, 95% CI: 1.04–1.23, p < 0.01) after diagnosis were associated with significantly increased all-cause mortality. Being obese prior to diagnosis of colorectal cancer was associated with increased colorectal cancer-specific mortality and all-cause mortality, whereas being obese after diagnosis was associated with increased all-cause mortality. The associations with being underweight may reflect reverse causation. Maintaining a healthy body weight should be discussed with colorectal cancer survivors.     

Association of metformin use with cancer incidence and mortality: A meta-analysis

PurposeTo assess the effect of metformin intake on cancer incidence and mortality.MethodsOriginal articles in English published until June 15, 2012 were searched for in electronic databases (MEDLINE, ISI Web of Science and EMBASE databases) and relevant reviews were examined. Meta-analysis was applied to calculate the summary relative risk (SRR) and their 95% confidence intervals (95% CI). Sensitivity analysis was conducted to assess the robustness of the pooled estimator. The risk of publication bias was assessed by the Egger regression asymmetry test.ResultsAccording to the eligibility criteria, 37 studies comprising 1,535,636 participants, were selected in terms of intervention and data of cancer incidence or mortality. Among metformin users compared with non-users, the SRR for overall-cancer incidence was 0.73 (95% CI, 0.64–0.83) and that for mortality was 0.82 (95% CI, 0.76–0.89). The risk reductions for liver, pancreatic, colorectal and breast cancer incidence were 78%, 46%, 23% and 6%, respectively. Also, metformin can reduce the mortality of liver cancer (SRR, 0.23; 95% CI, 0.09–0.60) and breast cancer (SRR, 0.63; 95% CI, 0.40–0.99). No statistically significant association between metformin and prostate cancer incidence was found.ConclusionsMetformin can reduce the incidence of overall cancer, liver cancer, pancreatic cancer, colorectal cancer and breast cancer as well as the mortality of overall cancer, liver cancer and breast cancer. No beneficial effect on prostate cancer incidence was found for meformin intake in the meta-analysis.     

REV3L single nucleotide variants lead to increased susceptibility towards non-small cell lung cancer in the population of Jammu and Kashmir

BackgroundNon-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for 80–85% of all lung cancer cases. Various genetic studies have associated REV3L (Protein reversion less 3-like) gene mutations, which encodes the catalytic subunit of error prone translesion synthesis polymerase zeta with cancer, including lung cancer; however, no such data is available from any North Indian population. In this study we attempted to screen the North Indian population of Jammu and Kashmir (J&K) for the potential role of REV3L gene polymorphisms in NSCLC.MethodsA total of four REV3L single nucleotide variants were selected for genotyping based on the available literature. The genotyping was carried out by using the TaqMan allele discrimination assay in 500 subjects (200 NSCLC patients and 300 age and sex matched healthy controls). The association of variants with NSCLC was evaluated by logistic regression.ResultsOut of the four REV3L variants genotyped; rs1002481, rs462779, and rs465646 were found significantly associated with NSCLC risk under the recessive model, with an Odds Ratio (OR) of 3.52(2.14–5.8 at 95% CI, p-value = 0.00000062), 3.7 (1.8–7.6 at 95% CI, p-value = 0.00031), and 2.2 (1.47–3.37 at 95% CI, p-value = 0.0003), respectively.DiscussionOur data supports a strong association between variants rs1002481, rs462779, rs465646 and NSCLC, indicating a potential role of these REV3L variants in increasing the risk for the development of NSCLC in the studied population. Although a first report from any Indian population, these variants have been previously reported to be associated with lung and colorectal cancers in different world populations. Our data along with the existing data supports the notation that these variants can be used as potential genetic predisposition markers.Availability of data and materialsData generated and analysed during study is not available publicly but can be made available from the corresponding author upon reasonable request.     

Association of caucasian-identified variants with colorectal cancer risk in singapore chinese

Background

Genome-wide association studies (GWAS) in Caucasians have identified fourteen index single nucleotide polymorphisms (iSNPs) that influence colorectal cancer (CRC) risk.

Methods

We investigated the role of eleven iSNPs or surrogate SNPs (sSNPs), in high linkage disequilibrium (LD, r²≥0.8) and within 100 kb vicinity of iSNPs, in 2,000 age- and gender-matched Singapore Chinese (SCH) cases and controls.

Results

Only iSNP rs6983267 at 8q24.21 and sSNPs rs6695584, rs11986063, rs3087967, rs2059254, and rs7226855 at 1q41, 8q23.3, 11q23.1, 16q22.1 and 18q21.1 respectively showed evidence of association with CRC risk, with odds ratios (OR) ranging from 1.13 to 1.40. sSNP rs827401 at 10p14 was associated with rectal cancer risk (OR = 0.74, 95% CI 0.63–0.88) but not disease prognosis (OR = 0.91, 95% CI 0.69–1.20). Interestingly, sSNP rs3087967 at 11q23.1 was associated with CRC risk in men (OR = 1.34, 95% CI 1.14–1.58) but not women (OR = 1.07, 95% CI: 0.88–1.29), suggesting a gender-specific role. Half of the Caucasian-identified variants, including the recently fine-mapped BMP pathway loci, BMP4, GREM1, BMP2 and LAMA 5, did not show any evidence for association with CRC in SCH (OR ∼1; p-value >0.1). Comparing the results of this study with that of the Northern and Hong Kong Chinese, only variants at chromosomes 8q24.21, 10p14, 11q23.1 and 18q21.1 were replicated in at least two out of the three Chinese studies.

Conclusions

The contrasting results between Caucasians and Chinese could be due to different LD patterns and allelic frequencies or genetic heterogeneity. The results suggest that additional common variants contributing to CRC predisposition remained to be identified.     

Association between GWAS-Identified Genetic Variations and Disease Prognosis for Patients with Colorectal Cancer

Genome-wide association studies (GWASs) have already identified at least 22 common susceptibility loci associated with an increased risk of colorectal cancer (CRC). This study examined the relationship between these single nucleotide polymorphisms (SNPs) and the clinical outcomes of patients with colorectal cancer. Seven hundred seventy-six patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. Twenty-two of the GWAS-identified SNPs were genotyped using a Sequenom MassARRAY. Among the 22 SNPs, two (rs1321311G>T in CDKN1A and rs10411210C>T in RHPN2) were significantly associated with the survival outcomes of CRC in a multivariate survival analysis. In a recessive model, the rs1321311 TT genotype (vs. GG + GT) and rs10411210 TT genotype (vs. CC + CT) were associated with a worse prognosis for disease-free survival (adjusted HR = 1.90; 95% confidence interval = 1.00-3.60; P = 0.050, adjusted HR = 1.94; 95% confidence interval = 1.05-3.57; P = 0.034, respectively) and overall survival (adjusted HR = 2.05; 95% confidence interval = 1.00-4.20; P = 0.049, adjusted HR = 2.06; 95% confidence interval = 1.05-4.05; P = 0.036, respectively). None of the other SNPs was significantly associated with any clinicopathologic features or survival. The present results suggest that the genetic variants of the CDKN1A (rs1321311) and RHPN2 (rs10411210) genes can be used as prognostic biomarkers for patients with surgically resected colorectal cancer.     

Healthy lifestyle,endoscopic screening,and colorectal cancer incidence and mortality in the United States: A nationwide cohort study

BackgroundHealthy lifestyle and screening represent 2 major approaches to colorectal cancer (CRC) prevention. It remains unknown whether the CRC-preventive benefit of healthy lifestyle differs by endoscopic screening status, and how the combination of healthy lifestyle with endoscopic screening can improve CRC prevention.Methods and findingsWe assessed lifestyle and endoscopic screening biennially among 75,873 women (Nurses’ Health Study, 1988 to 2014) and 42,875 men (Health Professionals Follow-up Study, 1988 to 2014). We defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption, and diet. We calculated hazard ratios (HRs) and population-attributable risks (PARs) for CRC incidence and mortality in relation to healthy lifestyle score according to endoscopic screening. Participants’ mean age (standard deviation) at baseline was 54 (8) years. During a median of 26 years (2,827,088 person-years) follow-up, we documented 2,836 incident CRC cases and 1,013 CRC deaths. We found a similar association between healthy lifestyle score and lower CRC incidence among individuals with and without endoscopic screening, with the multivariable HR per one-unit increment of 0.85 (95% CI, 0.80 to 0.90) and 0.85 (95% CI, 0.81 to 0.88), respectively (P-interaction = 0.99). The fraction of CRC cases that might be prevented (PAR) by endoscopic screening alone was 32% (95% CI, 31% to 33%) and increased to 61% (95% CI, 42% to 75%) when combined with healthy lifestyle (score = 5). The corresponding PAR (95% CI) increased from 15% (13% to 16%) to 51% (17% to 74%) for proximal colon cancer and from 47% (45% to 50%) to 75% (61% to 84%) for distal CRC. Results were similar for CRC mortality. A limitation of our study is that our study participants are all health professionals and predominantly whites, which may not be representative of the general population.ConclusionsOur study suggests that healthy lifestyle is associated with lower CRC incidence and mortality independent of endoscopic screening. An integration of healthy lifestyle with endoscopic screening may substantially enhance prevention for CRC, particularly for proximal colon cancer, compared to endoscopic screening alone.

Kai Wang and colleagues study contributions of healthy lifestyles and endoscopic screening to colorectal cancer outcomes.     

Colorectal cancer among farmers in the AGRICAN cohort study

ObjectivesSpecific farming types and tasks have rarely been studied in relation to colorectal cancer (CRC). We evaluated associations between 5 types of livestock and 13 types of crops in relation to CRC and its subsites within the Agriculture and Cancer (AGRICAN) study.MethodsAGRICAN cohort includes 181,842 agricultural workers living in 11 French geographical areas. Data on farming types and tasks was collected by self-administered questionnaires. We identified 2 609 CRC, 972 right colon, 689 left colon and 898 rectal incident cancer cases during follow-up from 2005 to 2015. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).ResultsSignificantly increased CRC risk was observed for farmers producing horses (HR=1.18, 95% CI 1.06–1.31), sunflower (HR=1.23, 95% CI 1.03–1.45) and field vegetables (HR=1.18, 95% CI 1.02–1.36). Positive associations were also observed for pig, poultry and wheat/barley. Some associations were observed only for specific subsites: left colon cancer was associated with fruit growing (HR=1.36, 95% CI 1.09–1.70) and potato (HR=1.28, 95% CI 1.05–1.57). Tasks related to livestock (animal care, insecticide treatment, disinfection of milking equipment and building) or to crop (haymaking, sowing, pesticide treatment, seed treatment, harvesting) were also associated with CRC. Duration and size of farming types/task increased the risk for some of the associations. Analysis stratified by sex suggested an interaction with several farming types/task.ConclusionsThe current study showed original and positive findings for several farming types and tasks and CRC risk, overall and by subsites.     

Association between red blood cell distribution width and long-term mortality among patients undergoing percutaneous coronary intervention with previous history of cancer

Abstract

Background: The number of patients suffering from coronary heart disease with cancer is rising. There is scarce evidence concerning the biomarkers related to prognosis among patients undergoing percutaneous coronary intervention (PCI) with cancer. Thus, the aim of this study was to investigate the association between red blood cell distribution width (RDW) and prognosis in this population.

Methods: A total of 172 patients undergoing PCI with previous history of cancer were enrolled in this retrospective study. The endpoint was long-term all-cause mortality. According to tertiles of RDW, the patients were classified into three groups: Tertile 1 (RDW <12.8%), Tertile 2 (RDW ≥12.8% and <13.5%) and Tertile 3 (RDW ≥13.5%).

Results: During an average follow-up period of 33.3 months, 29 deaths occurred. Compared with Tertile 3, mortality of Tertile 1 and Tertile 2 was significantly lower in the Kaplan–Meier analysis. In multivariate Cox regression analysis, RDW remained an independent risk factor of mortality (HR: 1.938, 95% CI: 1.295–2.655, p?<?0.001). The all-cause mortality in Tertile 3 was significantly higher than that in Tertile 1 (HR: 5.766; 95% CI: 1.426–23.310, p?=?0.014).

Conclusions: An elevated RDW level (≥13.5%) was associated with long-term all-cause mortality among patients undergoing PCI with previous history of cancer.     

Common genetic variants (rs4779584 and rs10318) at 15q13.3 contributes to colorectal adenoma and colorectal cancer susceptibility: evidence based on 22 studies

Several genome-wide association studies on colorectal cancer (CRC) have reported similar findings of a new susceptibility locus, 15q13.3. After that, a number of studies have reported that the rs4779584 and rs10318 polymorphisms at chromosome 15q13.3 have been implicated in CRC and colorectal adenoma (CRA) risk; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 22 studies involving a total of 48,468 CRC cases, 4,189 CRA cases, and 85,105 controls for the two polymorphisms to evaluate its effect on genetic susceptibility for CRC/CRA. Potential sources of heterogeneity and publication bias were also systematically explored. Overall, the summary odds ratio (OR) of rs4779584-T variant for CRC was 1.13 (95 % CI 1.09–1.16, P < 10^?5) and 1.15 (95 % CI 1.04–1.28, P = 0.006) for CRA. After stratified by ethnicity, significantly increased CRC risks were found for rs4779584 polymorphism among East Asians and Caucasians, while no significant associations were detected among African American and other ethnic populations. A meta-analysis of studies on the rs10318 polymorphism also showed significant overall association with CRC, yielding a per-allele OR of 1.13 (95 % CI 1.02–1.24, P = 0.02). In the subgroup analysis by ethnicity, significantly increased CRC risks were found in Caucasians; whereas no significant associations were found among East Asians and African Americans. This meta-analysis demonstrated that the rs4779584 and rs10318 polymorphism at 15q13.3 is a risk factor associated with increased CRC/CRA susceptibility, but these associations vary in different ethnic populations.     

Multigene Panel Sequencing Reveals Cancer-Specific and Common Somatic Mutations in Colorectal Cancer Patients: An Egyptian Experience

This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from patients with colorectal cancer. On top of this, the cohort included 20 biopsies from patients with non-specific mild to moderated colitis. Targeted DNA sequencing using a customized gene panel of 96 colorectal related genes running on the Ion Torrent NGS technology was used to process the samples. Our results revealed that 69% of all cases harbored at least one somatic mutation. Fifty-seven genes were found to carry 232 somatic non-synonymous variants. The most frequently pathogenic somatic mutations were localized in TP53, APC, KRAS, and PIK3CA. In total, 16 somatic mutations were detected in the CRC group and in either the IBD or CP group. In addition, our data showed that 51% of total somatic variants were CRC-specific variants. The average number of CRC-specific variants per sample is 2.4. The top genes carrying CRC-specific mutations are APC, TP53, PIK3CA, FBXW7, ATM, and SMAD4. It seems obvious that TP53 and APC genes were the most affected genes with somatic mutations in all groups. Of interest, 85% and 28% of the APC and TP53 deleterious somatic mutations were located in Exon 14 and Exon 3, respectively. Besides, 37% and 28% of the total somatic mutations identified in APC and TP53 were CRC-specific variants, respectively. Moreover, we identified that, in 29 somatic mutations in 21 genes, their association with CRC patients was unprecedented. Ten detected variants were likely to be novel: six in PIK3CA and four variants in FBXW7. The detected P53, Wnt/βcatenin, Angiogenesis, EGFR, TGF-β and Interleukin signaling pathways were the most altered pathways in 22%, 16%, 12%, 10%, 9% and 9% of the CRC patients, respectively. These results would contribute to a better understanding of the colorectal cancer and in introducing personalized therapies for Egyptian CRC patients.     

Single Nucleotide Variants in the Protein C Pathway and Mortality in Dialysis Patients

Background

The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients.

Methods

Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort.

Results

Factor V Leiden was associated with a 1.5-fold (95% CI 1.1–1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0–1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality.

Conclusion

Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.     

Understanding gastrointestinal cancer mortality disparities in a racially and geographically diverse population

BackgroundGastrointestinal (GI) cancers represent a diverse group of diseases. We assessed differences in geographic and racial disparities in cancer-specific mortality across subtypes, overall and by patient characteristics, in a geographically and racially diverse US population.MethodsClinical, sociodemographic, and treatment characteristics for patients diagnosed during 2009–2014 with colorectal cancer (CRC), pancreatic cancer, hepatocellular carcinoma (HCC), or gastric cancer in Georgia were obtained from the Surveillance, Epidemiology, and End Results Program database. Patients were classified by geography (rural or urban county) and race and followed for cancer-specific death. Multivariable Cox proportional hazards models were used to calculate stratified hazard ratios (HR) and 95% confidence intervals (CIs) for associations between geography or race and cancer-specific mortality.ResultsOverall, 77% of the study population resided in urban counties and 33% were non-Hispanic Black (NHB). For all subtypes, NHB patients were more likely to reside in urban counties than non-Hispanic White patients. Residing in a rural county was associated with an overall increased hazard of cancer-specific mortality for HCC (HR = 1.15, 95% CI = 1.02–1.31), pancreatic (HR = 1.11, 95% CI = 1.03–1.19), and gastric cancer (HR = 1.17, 95% CI = 1.03–1.32) but near-null for CRC. Overall racial disparities were observed for CRC (HR = 1.18, 95% CI = 1.11–1.25) and HCC (HR = 1.12, 95% CI = 1.01–1.24). Geographic disparities were most pronounced among HCC patients receiving surgery. Racial disparities were pronounced among CRC patients receiving any treatment.ConclusionGeographic disparities were observed for the rarer GI cancer subtypes, and racial disparities were pronounced for CRC. Treatment factors appear to largely drive both disparities.     

Polymorphisms in the selenoprotein S and 15-kDa selenoprotein genes are associated with altered susceptibility to colorectal cancer

Selenium (Se), a dietary trace metal essential for human health, is incorporated into ~25 selenoproteins including selenoprotein S (SelS) and the 15-kDa selenoprotein (Sep15) both of which have functions in the endoplasmic reticulum protein unfolding response. The aim of this study was to investigate whether genetic variants in such selenoprotein genes are associated with altered risk of colorectal cancer (CRC). A Korean population of 827 patients with CRC and 733 healthy controls was genotyped for 7 SNPs in selenoprotein genes and one SNP in the gene encoding manganese superoxide dismutase using Sequenom technology. Multivariate logistic regression analysis showed that after adjustment for lifestyle factors three SNP variants were associated with altered disease risk. There was a mean odds ratio of 2.25 [95% CI 1.13,4.48] in females homozygous TT for rs34713741 in SELS with the T variant being associated with higher risk of rectal cancer, and odds ratios of 2.47 and 2.51, respectively, for rs5845 and rs5859 in SEP15 with the minor A and T alleles being associated with increased risk of male rectal cancer. The data indicate that the minor alleles for rs5845, rs5859 and rs34713741 are associated with increased rectal cancer risk and that the effects of the three SNPs are dependent on gender. The results highlight potential links between Se, the function of two selenoproteins involved in the protein unfolding response and CRC risk. Further studies are required to investigate whether the effects of the variants on CRC risk are also modulated by dietary Se intake.     

NOD1 and NOD2 Genetic Variants in Association with Risk of Gastric Cancer and Its Precursors in a Chinese Population

BackgroundGenetic variants of nucleotide-binding oligomerization domain-containing protein (NOD) may influence the outcome of Helicobacter pylori (H. pylori) infection and gastric carcinogenesis. To explore genetic variants of NOD1 and NOD2 in association with gastric cancer (GC) and its precursors, a population-based study was conducted in Linqu County, China.MethodsTagSNPs of NOD1 and NOD2 were genotyped by Sequenom MASS array in 132 GCs, and 1,198 subjects with precancerous gastric lesions, and were correlated with evolution of gastric lesions in 766 subjects with follow-up data.ResultsAmong seven tagSNPs, NOD1 rs2709800 and NOD2 rs718226 were associated with gastric lesions. NOD1 rs2709800 TG genotype carriers had a decreased risk of intestinal metaplasia (IM, OR: 0.53; 95% CI: 0.31–0.92), while NOD2 rs718226 G allele (AG/GG) showed increased risks of dysplasia (DYS, OR: 2.96; 95% CI: 1.86–4.71) and GC (OR: 2.35; 95% CI: 1.24–4.46). Moreover, an additive interaction between rs718226 and H. pylori was found in DYS or GC with synergy index of 3.08 (95% CI: 1.38–6.87) or 3.99 (95% CI: 1.55–10.22), respectively. The follow-up data indicated that NOD2 rs2111235 C allele (OR: 0.52; 95% CI: 0.32–0.83) and rs7205423 G allele (OR: 0.56; 95% CI: 0.35–0.89) were associated with decreased risk of progression in H. pylori-infected subjects.ConclusionsNOD1 rs2709800, NOD2 rs718226, rs2111235, rs7205423 and interaction between rs718226 and H. pylori infection may be related to risk of gastric lesions.