Patricia Carrera

Relevance of GSTM1, GSTT1, and GSTP1 gene polymorphisms to gastric cancer susceptibility and phenotype

Human glutathione S-transferases (GSTs) are phase II metabolizing enzymes that play a key role in protecting against cancer by detoxifying numerous potentially cytotoxic/genotoxic compounds. The genes encoding the human GST isoenzymes GSTM(mu)1, GSTT(theta)1 and GSTP(pi)1 harbour polymorphisms, which have been considered important modifiers of the individual risk for environmentally induced cancers such as gastric cancer (GC). However, results are inconsistent among studies from different geographic areas and ethnic groups. Our goal was to perform a nationwide, case-control study in Spain to evaluate the relevance of several functional GST gene polymorphisms and environmental factors to GC risk and phenotype. DNA from 557 GC patients and 557 sex- and age-matched healthy controls (HC) was typed for two deletions in the GSTM1 and GSTT1 genes and two SNPs in the GSTP1 gene (rs1695 and rs1138272) using polymerase chain reaction-restriction fragment length polymorphism methods. Logistic regression analysis identified Helicobacter pylori infection with CagA strains [odds ratio (OR): 2.36; 95% confidence interval (CI): 1.78-3.15], smoking habit (OR: 2.10; 95% CI: 1.48-2.97) and family history of GC (OR: 3.2; 95% CI: 2.02-5.16) as independent risk factors for GC. No differences in the frequencies of GSTM1 or GSTT1 null genotypes were observed between cases and controls (GSTM1: 50.8% vs. 48%; GSTT1: 21.5% vs. 21%). Moreover, simultaneous carriage of both, the GSTM1 and the GSTT1 null genotypes, was almost identical in both groups (10.7% in GC vs. 10.6% in HC). In addition, no significant differences in GSTP1 Ile105Val (rs1695) and GSTP1 Val114Ala (rs1138272) genotype distribution were observed between GC patients and controls. Subgroup analysis for age, gender, Helicobacter pylori status, smoking habits, family history of GC, anatomic location and histological subtype revealed no significant association between GST variants and GC risk. Our results show that the GST polymorphisms evaluated in this study are not relevant when determining the individual susceptibility to GC or phenotype in a South-European population.

Prognostic Role of Host Cyclooxygenase and Cytokine Genotypes in a Caucasian Cohort of Patients with Gastric Adenocarcinoma

Background Genetic factors influencing the prognosis of gastric adenocarcinoma (GAC) are not well known. Given the relevance of cytokines and other pro-inflammatory mediators in cancer progression and invasiveness, we aimed to assess the prognostic role of several functional cytokine and cyclooxygenase gene polymorphisms in patients with GAC. Methodology Genomic DNA from 380 Spanish Caucasian patients with primary GAC was genotyped for 23 polymorphisms in pro-inflammatory (IL1B, TNFA, LTA, IL6, IL12p40), anti-inflammatory (IL4, IL1RN, IL10, TGFB1) cytokine, and cyclooxygenase (PTGS1 and PTGS2) genes by PCR, RFLP and TaqMan assays. Clinical and histological information was collected prospectively. Survival curves were estimated by the Kaplan-Meier method and compared using the log rank test. Outcome was determined by analysis of Cox proportional hazards, adjusting for confounding factors. Results The median follow-up period and median overall survival (OS) time were 9.9 months (range 0.4–120.3) and 10.9 months (95% CI: 8.9–14.1), respectively. Multivariate analysis identified tumor stages III (HR, 3.23; 95% CI:2–5.22) and IV (HR, 5.5; 95% CI: 3.51–8.63) as independent factors associated with a significantly reduced OS, whereas surgical treatment (HR: 0.44; 95%CI: 0.3–0.6) was related to a better prognosis of the disease. Concerning genetic factors, none of the 23 polymorphisms evaluated in the current study did influence survival. Moreover, no gene-environment interactions on GAC prognosis were observed. Conclusions Our results show that, in our population, the panel of selected pro- and anti-inflammatory cytokine, and cyclooxygenase gene polymorphisms are not relevant in determining the prognosis of gastric adenocarcinoma.

Short- and long-term clinical outcomes of self-expandable metal stents inserted for colorectal obstruction and efficacy of different insertion techniques

OBJECTIVES (1) To evaluate the short- and long-term clinical outcomes of patients after colorectal stent placement and (2) to assess the safety and efficacy of the stents for the resolution of colorectal obstruction according to the insertion technique. METHODS Retrospective cohort study which included 177 patients with colonic obstruction who underwent insertion of a stent. RESULTS A total of 196 stents were implanted in 177 patients. Overall, the most common cause of obstruction was colorectal cancer (89.3%). Ninety-two stents (47%) were placed by radiologic technique and 104 (53%) by endoscopy under fluoroscopic guidance. Technical success rates were 95% in both groups. Clinical success rates were 77% in the radiological group and 81% in the endoscopic group (p>0.05). The rate of complications was higher in the radiologic group compared with the endoscopic group (38% vs 20%, respectively; p=0.006). Among patients with colorectal cancer (158), 65 stents were placed for palliation but 30% eventually required surgery. The multivariate analysis identified three factors associated with poorer long-term survival: tumor stage IV, comorbidity and onset of complications. CONCLUSIONS Stents may be an alternative to emergency surgery in colorectal obstruction, but the clinical outcome depends on the tumor stage, comorbidity and stent complications. The rate of definitive palliative stent placement was high; although surgery was eventually required in 30%. Our study suggests that the endoscopic method of stent placement is safer than the radiologic method.

Fecal Hemoglobin Concentration, a Good Predictor of Risk of Advanced Colorectal Neoplasia in Symptomatic and Asymtomatic Patients

Citation: Navarro M, Hijos G, Ramirez T, Omella I, Carrera-Lasfuentes P and Lanas Á (2019) Fecal Hemoglobin Concentration, a Good Predictor of Risk of Advanced Colorectal Neoplasia in Symptomatic and Asymptomatic Patients. Front. Med. 6:91. doi: 10.3389/fmed.2019.00091 Fecal Hemoglobin Concentration, a Good Predictor of Risk of Advanced Colorectal Neoplasia in Symptomatic and Asymptomatic Patients

290 Relevance of DNA Repair Polymorphisms As Genetic Markers of Gastric Cancer Susceptibility and Prognosis in Caucasians

Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality through the endoscopic detection and removal of colorectal adenomas. Still, these patients are at increased risk for developing metachronous adenomas or even cancer, with the recurrence rate reaching the 50%. The pleiotropic effects of higher levels of PGE2 contribute to key steps of cancer development, including cell proliferation, angiogenesis, invasiveness and migration, inhibition of apoptosis and immunosurveillance as a refletion of deregulation of ATP-binding cassete sub-family c member 4 (ABCC4) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1) genes responsable for carrying PGE2 accross the membrane. To evaluate the influence of genetic polymorphisms in ABCC4 and SLCO2A1 on the risk and time for colorectal adenoma recurrence a retrospective case-cohort study was designed gathering 195 patients diagnosed with colorectal adenomas. Adenoma reccurence was defined has the diagnosis of an adenoma after a total normal colonoscopy at least one year after the initial diagnosis. Thirty-three tagSNPs were characterized using the MassARRAY iPLEX Gold technology based on multiplex amplification followed by mass-spectrometric product separation. Three tagSNPs were identified as susceptibility biomarkers for colorectal adenoma recurrence after a bootstrap analysis. The rs1131598GG homozygous genotype of SLCO2A1 gene was associated with an enhanced risk of 6.3 (95%CI:1.31-30.0, P=0.021). In contrast and under a dominant model of inheritance, the rs1751031 and rs9524821 polymorphisms in ABCC4 gene displayed a protective behaviour (OR=0.29, 95%CI:0.12-0.72, P=0.007 and OR=0.42, 95%CI:0.19-0.93, P=0.033, respectively). Furthermore, when stratifying patients considering the endoscopic findings at baseline colonoscopy, low-risk individuals carriers of rs2274403AA genotype in ABCC4 gene had a lower interval until recurrence (85 (29140) vs 122 (109-135), P=0.011) with 44% of metachronous tumors developing by 36 months (vs 23% for AG/GG). This study demonstrates for the first time the involvement of genetic variants in PGE2 transporters in colorectal adenoma recurrence. The incorporation of genetically-based approaches might allow an optimization of current risk models for the development of metachronous colorectal adenomas or even more advanced lesions possible laeding to a decrease in CRC burden and mortality.