Abstract Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri‐miRNA, 7 pre‐miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression‐free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04–1.80]; P = 0.02), hsa‐mir‐124‐1 rs531564 (aHR = 0.60, 95% CI: [0.53–0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28–0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03–1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01–1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa‐mir‐124‐1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa‐mir‐124‐1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma.

Recent studies have made significant advances in understanding the mechanisms of gut microbiota involved in human health and disease [1,2].Now the gut microbiota has been recognized as a key player in a broad spectrum of human diseases from obesity associated liver and cardiovascular diseases to mental development and psychiatric diseases [3,4].Accordingly, modulations of gut microbial diversity and composition are expected to improve human health and to provide novel therapeutic modalities for human disease.The gut microbial modulators can be simply specific diets and drinks, natural tea and Chinese herbs, or specialized prebiotics and probiotics.In this special issue, authors presented a number of very interesting studies on changes of gut microbiota in digestive diseases.These review and original articles of research and clinical studies cover a range of topics, including the pathogenesis of alcoholic and nonalcoholic fatty liver diseases (NAFLD), the outcome of intestinal bacterial translocation in advanced cirrhosis, the gut microbiota changes in an animal colitis model after treatment with a monoclonal antibody, and fecal microbiota transplantation (FMT) in elderly patients with refractory Clostridium difficile infection.In these articles, authors have described mechanisms of disease development as well as therapeutic effects of specific antibodies, probiotics, and FMT.While we know the simple cause of alcoholic fatty liver disease (AFLD), its pathogenesis is complicated and it

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) in PNPLA3 and rs58542926 (Glu167Lys) in TM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression.

Background: The drug transporter ABCC2 is upregulated in non-small cell lung cancer (NSCLC) and implicated in platinum resistance. We evaluated the association between germline polymorphisms in the ABCC2 gene and survival outcomes of platinum-treated advanced NSCLC patients.Material and methods: Ten candidate and tagging germline polymorphisms in the ABCC2 gene were genotyped in a discovery cohort of 170 platinum-treated stage IV NSCLC patients from the Princess Margaret Cancer Centre. Associations with overall survival were assessed using multivariate Cox proportional hazard models adjusted for prognostic variables. To validate our results, we analyzed the association of the two top polymorphisms in the ABCC2 gene on survival outcomes of 219 stage IIIB-IV NSCLC patients enrolled on the NCIC Clinical Trials Group BR. 24 clinical trial.Results: Only one polymorphism was validated across both cohorts for an association with overall survival: the A allele of the ABCC2 polymorphism, rs8187710 (4544G > A), was associated with adverse overall survival (adjusted hazard ratio [aHR] 2.22; 95% CI: 1.2-4.0; p = 0.009) among our stage IV NSCLC patients. A significant association with overall survival (aHR 1.73; 95% CI: 1.0-2.9; p = 0.036) was observed for the same ABCC2 polymorphism in the BR. 24 validation cohort. No other ABCC2 polymorphisms were associated with outcome.Conclusion: The ABCC2 polymorphism, rs8187710 (4544G > A), is associated with overall survival in platinum-treated advanced NSCLC patients. Additional studies are needed to evaluate the predictive versus prognostic nature of this relationship, and to explore the functional effect of this polymorphism on the pharmacokinetics of platinum drugs. (C) 2016 Published by Elsevier Ltd.

Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis and median OS and PFS were 20 and 12 months, respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality. Validation and evaluation of this association in other cancer sites are warranted.

Declaration of Conflicting Interests:The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.Funding:TvR was supported by an Alberta Innovates Doctoral Graduate Student Scholarship and an Antoine Noujaim Graduate Scholarship.

Aim: Bevacizumab improves progression-free survival in advanced stage ovarian cancer patients treated with carboplatin and paclitaxel. We evaluated the role of genetic variants in modifying the benefit of bevacizumab in ICON7, one of the key clinical trials to describe this benefit in ovarian cancer. Using a hypothesis-agnostic genome-wide association study (GWAS) approach, we evaluated association of genetic markers with survival.

Aim: Neurotoxicity is known of both platinum and taxane agents. Factors associated with increased risk of peripheral neuropathy (PN) include cumulative dose and comorbidity. Individual genetic susceptibility may play a role. Applying GWAS methods to patients of ICON7 (NCT00483782), a phase 3 ovarian cancer trial of adding bevacizumab to carboplatin and paclitaxel, we evaluated the association of heritable genetic markers with PN.

Introduction: Polymorphisms within miRNA and in genes regulating miRNA biogenesis can regulate a variety of cancer pathways in EC patients. Comprehensive pathway analyses of miRNA-related genes were performed on EC outcomes. Methods: 324 EC patients from Princess Margaret Hospital (Toronto, Canada) were screened for 62 single nucleotide polymorphisms (SNPs) in 21 miRNA or miRNA biogenesis pathway genes. Multivariate Cox-proportional hazard models, adjusted for key prognostic factors evaluated the association of each SNP with overall survival (OS) and progression free survival (PFS). Significant SNPs were further analysed for joint effects, and also in subgroup and pathway analyses. All results were internally validated through bootstrapping. Results: Five polymorphisms belonging to the miRNA biogenesis pathway and one in a miRNA were nominally associated with OS or PFS, where adjusted hazard ratios (aHR) were between 1.23-1.41 for each comparison; p=0.003-0.04: AGO1 (rs595961; chromosome (chr) 1), GEMIN3 (rs197412; chr1) CD86 (rs17281995; chr 3) hs-miRNA-26a1 (rs7372209; chr 3), GEMIN4 (rs7813 and rs910924; chr 17). Joint effect analysis of SNPs in the same chromosome found additive effects of these risk alleles (RA) on outcome: chr 1 (2-4 vs 0-1: aHROS=1.82 [1.21-2.75], p=0.004), chr 3 (3-4 vs 0: aHROS=4.07 [1.91-8.67], p=0.003), chr 17 (4 vs 0: aHRPFS=2.21 [1.13-4.31], p=0.02). Pathway based analysis found each additional RA conferring a strong additive effect on OS (per 2 RA: aHR=1.50 [1.25-1.81], p=1.9x10E-5). Results on PFS were similar, with aHRPFS per 2RA of 1.51 [1.26-1.82], p=1.3x10E-5. Internal validation found consistent results for all analyses. Exploratory subgroup analysis identified two SNPs that had differential effects on OS based on histology: for adenocarcinomas, the aHR for KIAA0423 (rs1053667) was 0.51 [0.28-0.96], p=0.03, while for squamous cell carcinomas, the aHR was 7.36 [2.07-26.1], p=0.002. Similarly, for DICER (rs13078), aHRadenocarcinoma=0.96 [0.72-1.28], p=0.78 vs aHRsquamous=2.51[1.21-5.21], p=0.01). In subset analyses, hsa-mir-30a (rs1358379), hsa-mir-492 (rs2289030), hsa-mir-499 (rs3746444), and DGCR8 (rs1640299) were significantly associated with different outcomes by nodal status. Conclusion: We identified the miRNA biogenesis pathway as having an important role in the prognosis of EC patients, with a 50% increase in death or disease progression when carrying two additional miRNA risk alleles. Although some of the identified polymorphisms have been previously associated with risk or prognosis in other cancer disease sites, we report for the first time, their associations with esophageal cancer prognosis. Citation Format: Lawson Eng, Olusola O. Faluyi, Xin Qiu, Dangxiao Cheng, Daniel J. Renouf, Lorin Dodbiba, Sevtap Savas, Sharon Marsh, Jennifer J. Knox, Gail E. Darling, Rebecca KS Wong, Wei Xu, Geoffrey Liu, Abul K. Azad. Polymorphisms in microRNA (miRNA) pathways and survival in esophageal cancer (EC) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2562. doi:10.1158/1538-7445.AM2013-2562 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

32 Background: Better understanding of the biology of esophageal cancer may help improve its treatment. MicroRNAs (miRs) regulate mRNA and can exert some influence on carcinogenesis. Identification of the microRNAs which regulate esophageal cancer development could potentially yield alternative therapeutic options. Objectives: We evaluated polymorphisms in miRs, miR biogenesis, binding sites of miR and their role in the survival of esophageal cancer patients. Methods: 324 esophageal cancer patients of all stages and histological subtypes were evaluated. Using Illumina Custom GoldenGate, 43 polymorphisms in miR pathways were evaluated. Cox proportional hazards models adjusted for clinical prognostic variables and determined the association of polymorphisms with overall survival (OS) and progression free survival (PFS). Adjusted hazard ratio (aHR) and 95% confidence intervals (CI) were calculated. Results: Among our patients, 83% were male while the mean age was 65 years. 73% had adenocarcinomas while 33.6% had advanced tumors (Stage IV). The median PFS was 1.20 years, while median OS was 2.17 years. After adjustment for clinical variables, a 5’UTR polymorphism in pri-mir26a-1 (rs7372209) was significantly associated with reduced PFS [aHR=0.78, CI:0.62-0.98, p=0.04] and OS [aHR 0.71 (0.56-0.89), p=0.003]. Three other polymorphisms were significantly associated with OS but not PFS: these included two polymorphisms of miR processing genes, DDX20 (rs197412) [aHR 1.31 (1.04-1.64), p=0.02] and EIF2C1 (rs595961) [aHR 0.76 (0.60-0.97), p=0.03] as well as the CD86 3’UTR C>G (rs17281995) polymorphism, which has been predicted to affect the binding of miR337, miR582, miR200a, miR184, and miR212 [aHR 1.38 (1.03-1.85), p=0.03]. Conclusions: We report the initial association of miR related polymorphisms with survival in esophageal cancer. We plan to explore additional relationships and validate these findings in other datasets.

Pharmacogenomics, driven by advances in genomics, helps to explain patients' individual variability in response to therapies. Personalized medicine, the application of the increasing understanding of pharmacogenomics, and information technology are intertwined from discovery to delivery at point of care, through to tracking clinical outcomes. Although exemplary cases of personalized medicine adoption demonstrate patient benefit and cost-effectiveness, a remaining barrier to large-scale real-world uptake of this novel approach in medicine is policy change. At point-of-care implementation, case studies will need to measure personalized medicine application outcomes of relevance to policy-makers and as evidence of clinical utility. Assessments need to be consistent across case studies. Standardizing specifications for case studies will better inform policy-makers performing economic evaluations on the use of personalized medicine.

Multiple drug strategies for many cancer types are now readily available and there is a clear need for tools to inform decision making on therapy selection. Although there is still a long way to go before pharmacogenomics achieves the goal of individualized selection of cancer treatment, promising progress is being made. Genetic testing for thiopurine methyltransferase (TPMT) variant alleles in patients prior to mercaptopurine administration, and for UGT1A1*28 in patients prior to administration of irinotecan therapy, along with the instigation of genotype-guided clinical trials (e.g. TYMS) are important advances in cancer pharmacogenomics. Markers for the toxicity and efficacy of many oncology drugs remain unknown; however, the examples highlighted here suggest progress is being made towards the incorporation of pharmacogenomics into clinical practice in oncology.

7586 Background: Two potentially important host pathways in lung cancer systemic therapy are: (i) the pharmacogenetic pathway of platinum agents (DNA repair, metabolism, and multidrug resistance genes); and (ii) the vascular endothelial growth factor (VEGF) pathway. We investigated the relationship between SNPs in these two pathways and clinical outcome in platinum-treated NSCLC patients. Methods: 188 platinum-treated Stage IV NSCLC patients underwent SNP genotyping for the platinum-related (48 SNPs in 7 genes) and VEGF (64 SNPs in 3 genes) pathways. SNPs were selected from the literature and through tagging. Association of SNPs and overall (OS) and progression free survival (PFS) were assessed using multivariate Cox proportional hazards models. Results: 72% were Caucasian; 73%, adenocarcinoma; 92%, ECOG PS 0-1; median age, 60 years; 54% received > one line of systemic therapy; 10% received anti-VEGF therapy/placebo; Median OS, 1.3 yrs; median follow up, 2.2 yrs. The top significant SNPs in the platinum-related pathway were in ABCC2 (rs8187710 and rs2756109, r2=0.68). The G variants of the top SNP, ABCC2 rs8187710 (4554G>A), were associated with worse OS (adjusted hazard ratio [aHR], 2.62; 95%CI: 1.5-4.5; p=0.0005) and PFS (aHR, 1.97; 95%CI: 1.2-3.4; p=0.01). Functionally, 4554G>A impairs ATP-ase activity and is associated with higher cellular accumulation of ABCC2 substrates [PMID: 22027652]; furthermore, ABCC2 expression is associated with cisplatin resistance and clinical outcome in other cancers [PMID: 17145840]. Within the VEGF pathway, the top significant SNPs were in the same haplotype block of VEGFR1/FLT1 (rs1324057, rs7324547, r2=1.0): for rs1324057, the aHR for OS was 1.59 (95%CI 1.2-2.1); p=0.001; and the aHR for PFS, 1.48 (95%CI 1.1-1.9); p=0.004. VEGFR1/FLT1 rs7324547 has been associated with esophageal cancer risk [PMID: 21751195], but has not been assessed in lung cancer. Conclusions: SNPS of the VEGFR1 and ABCC2 genes are strongly associated with OS and PFS in this cohort of platinum-treated advanced NSCLC patients. Future studies should assess whether these are predictive or prognostic markers.

Purpose. Numerous studies have explored the potential role of genetic polymorphisms as predictive or prognostic biomarkers in gynecologic malignancies. A systematic review for all eligible polymorphisms has not yet been reported. The aim of this study was to summarize the current status of the field and provide direction for future research.Design. We searched literature databases (MEDLINE, EMBASE, Cochrane) from 2006 to April 2011 to identify studies evaluating the association between gene polymorphisms and clinical outcome in ovarian, endometrial, cervical, or vulvar cancer. The main outcome measures were overall survival (OS) and progression-free survival (PFS). Studies reporting relationships between polymorphisms and toxicity were also included.Results. Sixty two studies met the inclusion criteria. The median sample size was 140. Most of the included studies (n = 50, 81%) were conducted in ovarian cancer patients. Almost a third assessed potential predictive associations between gene polymorphism and outcome in ovarian cancer. The most commonly evaluated genes were ERCC1, VEGF, ABCB1 (MDR), and GSTP1. Most studies (n =44, 71%) were observational case-series. Only four studies (6%) included a validation arm and patient population ethnicity was explicitly stated only in 27% of included studies.Conclusion. No consistent association between any gene polymorphism and clinical outcome in gynecological cancers has been found across studies. There is incomplete adherence to the REMARK guidelines and inadequate methodology reporting in most studies. Moving forward, analysis of large trial-based clinical samples; adherence to the highest methodological standards, and focus on validation analyses are necessary to identify clinically useful pharmacogenomic biomarkers of outcome. (C) 2011 Elsevier Inc. All rights reserved.

Typically, chemotherapy selection takes into account patient demographic data, including disease symptoms, family history, environmental factors and concurrent medications. Although validated and approved genomics tests are available for targeted therapeutics, a major challenge facing healthcare is the ability to process the genomic data in the patient's context and to return clinically interpretable dosing guidance to the physician in a realistic time frame. Delivery of these targeted therapeutics, made possible by clinical decision support systems connected to an electronic health record may help drive both the acceptance and adaptation of an electronic health record system, as well as provide personalized information at point-of-care, as part of the routine workflow. The realization of targeted therapeutics will depend on the concerted efforts of stakeholder groups as they address political, ethical, socioeconomical and technical challenges to achieve personalized medicine adoption through real-world implementation.

Thorn, Caroline F.; Oshiro, Connie; Marsh, Sharon; Hernandez-Boussard, Tina; McLeod, Howard; Klein, Teri E.; Altman, Russ B. Author Information