The mediating role of combined lifestyle factors on the relationship between education and gastric cancer in the Stomach cancer Pooling (StoP) Project.

BACKGROUND: The causal pathway between high education and reduced risk of gastric cancer (GC) has not been explained. The study aimed at evaluating the mediating role of lifestyle factors on the relationship between education and GC METHODS: Ten studies with complete data on education and five lifestyle factors (smoking, alcohol drinking, fruit and vegetable intake, processed meat intake and salt consumption) were selected from a consortium of studies on GC including 4349 GC cases and 8441 controls. We created an a priori score based on the five lifestyle factors, and we carried out a counterfactual-based mediation analysis to decompose the total effect of education on GC into natural direct effect and natural indirect effect mediated by the combined lifestyle factors. Effects were expressed as odds ratios (ORs) with a low level of education as the reference category. RESULTS: The natural direct and indirect effects of high versus low education were 0.69 (95% CI: 0.62-0.77) and 0.96 (95% CI: 0.95-0.97), respectively, corresponding to a mediated percentage of 10.1% (95% CI: 7.1-15.4%). The mediation effect was limited to men. CONCLUSIONS: The mediation effect of the combined lifestyle factors on the relationship between education and GC is modest. Other potential pathways explaining that relationship warrants further investigation.

Tea consumption and gastric cancer: a pooled analysis from the Stomach cancer Pooling (StoP) Project consortium.

BACKGROUND: Evidence from epidemiological studies on the role of tea drinking in gastric cancer risk remains inconsistent. We aimed to investigate and quantify the relationship between tea consumption and gastric cancer in the Stomach cancer Pooling (StoP) Project consortium. METHODS: A total of 9438 cases and 20,451 controls from 22 studies worldwide were included. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of gastric cancer for regular versus non-regular tea drinkers were estimated by one and two-stage modelling analyses, including terms for sex, age and the main recognised risk factors for gastric cancer. RESULTS: Compared to non-regular drinkers, the estimated adjusted pooled OR for regular tea drinkers was 0.91 (95% CI: 0.85-0.97). When the amount of tea consumed was considered, the OR for consumption of 1-2 cups/day was 1.01 (95% CI: 0.94-1.09) and for >3 cups/day was 0.91 (95% CI: 0.80-1.03). Stronger inverse associations emerged among regular drinkers in China and Japan (OR: 0.67, 95% CI: 0.49-0.91) where green tea is consumed, in subjects with H. pylori infection (OR: 0.68, 95% CI: 0.58-0.80), and for gastric cardia cancer (OR: 0.64, 95% CI: 0.49-0.84). CONCLUSION: Our results indicate a weak inverse association between tea consumption and gastric cancer.

Salt intake and gastric cancer: a pooled analysis within the Stomach cancer Pooling (StoP) Project.

PURPOSE: Previous studies show that consuming foods preserved by salting increases the risk of gastric cancer, while results on the association between total salt or added salt and gastric cancer are less consistent and vary with the exposure considered. This study aimed to quantify the association between dietary salt exposure and gastric cancer, using an individual participant data meta-analysis of studies participating in the Stomach cancer Pooling (StoP) Project. METHODS: Data from 25 studies (10,283 cases and 24,643 controls) from the StoP Project with information on salt taste preference (tasteless, normal, salty), use of table salt (never, sometimes, always), total sodium intake (tertiles of grams/day), and high-salt and salt-preserved foods intake (tertiles of grams/day) were used. A two-stage approach based on random-effects models was used to pool study-specific adjusted (sex, age, and gastric cancer risk factors) odds ratios (aORs), and the corresponding 95% confidence intervals (95% CI). RESULTS: Gastric cancer risk was higher for salty taste preference (aOR 1.59, 95% CI 1.25-2.03), always using table salt (aOR 1.33, 95% CI 1.16-1.54), and for the highest tertile of high-salt and salt-preserved foods intake (aOR 1.24, 95% CI 1.01-1.51) vs. the lowest tertile. No significant association was observed for the highest vs. the lowest tertile of total sodium intake (aOR 1.08, 95% CI 0.82-1.43). The results obtained were consistent across anatomic sites, strata of Helicobacter pylori infection, and sociodemographic, lifestyle and study characteristics. CONCLUSION: Salty taste preference, always using table salt, and a greater high-salt and salt-preserved foods intake increased the risk of gastric cancer, though the association was less robust with total sodium intake.

Perianal Fistula After Ileoanal Pouch in Patients With Ulcerative Colitis: A Review of 475 Patients Operated on at a Major IBD Center.

BACKGROUND: Ileoanal pouch anastomosis is the surgical treatment of choice for patients with intractable ulcerative colitis. Perianal disease is a feature that is often present in Crohn's disease and infrequently in ulcerative colitis. OBJECTIVE: The aim of this study is to identify the incidence and factors associated with the development of postoperative perianal fistula in patients undergoing ileoanal pouch anastomosis for ulcerative colitis. DESIGN: A prospectively collected database at the time of surgery with subsequent follow-up was utilized. SETTING: The study was conducted at a high-volume single institution. PATIENTS: We studied a series of 475 consecutive patients with preoperative diagnosis of ulcerative colitis who underwent ileoanal pouch anastomosis. MAIN OUTCOME MEASURES: The incidence of postoperative perianal fistula and the factors correlating with its development were primary outcome measures of the study. RESULTS: The overall number of patients developing perianal fistulas was 44 of 475 (9%). Eleven patients with perianal fistula (25%) required return to ileostomy, of which 7 had pouch excision. Patients who developed a postoperative perianal fistula had a younger age at the onset of disease, had a lower age at index surgery, and were more likely to be subsequently classified as indeterminate colitis or Crohn's disease. Patients developing perianal fistulas were also more likely to develop partial dehiscence or stricture of the ileoanal anastomosis. LIMITATIONS: This study spans nearly 40 years during which the surgical procedure evolved. CONCLUSIONS: Young age at the onset of disease, lower age at surgery, and postoperative diagnosis of Crohn's disease and indeterminate colitis were the factors correlating with perianal fistulas. Delayed healing of the ileoanal anastomosis with partial separation and/or stricture also correlated with the onset of perianal fistulas. The severity of rectal inflammation at the time of surgery or the presence of stapled versus handsewn anastomosis did not correlate with the development of perianal fistulas. See Video Abstract at http://links.lww.com/DCR/B705. FSTULA PERIANAL POSTERIOR A RESERVORIO ILEOANAL EN PACIENTES CON COLITIS ULCERATIVA UNA REVISIN DE PACIENTES OPERADOS EN UN CENTRO PRINCIPAL DE EII: ANTECEDENTES:El reservorio ileoanal es el tratamiento quirúrgico de elección para los pacientes con colitis ulcerativa intratable. La enfermedad perianal es una característica que a menudo está presente en la enfermedad de Crohn y con poca frecuencia en la colitis ulcerativa.OBJETIVO:El objetivo del estudio es identificar la incidencia y los factores asociados con el desarrollo de fístula perianal posoperatoria en pacientes sometidos a reservorio ileoanal por colitis ulcerativa.DISEÑO:Base de datos recopilada prospectivamente en el momento de la cirugía con seguimiento subsecuente.ENTORNO CLÍNICO:El estudio se llevó a cabo en una única institución de gran volumen.PACIENTES:Estudiamos una serie de 475 pacientes consecutivos con diagnóstico preoperatorio de colitis ulcerativa a los que se les realizó reservorio ileoanal.PRINCIPALES MEDIDAS DE VALORACIÓN:La incidencia de fístula perianal posoperatoria y los factores que se correlacionan con su desarrollo fueron las principales medidas de resultado del estudio.RESULTADOS:El número total de pacientes que desarrollaron fístulas perianales fue 44 de 475 (9%). Once pacientes con fístula perianal (25%) requirieron volver a la ileostomía, de los cuales 7 tuvieron resección del reservorio. Los pacientes que desarrollaron fístula perianal posoperatoria tenían edad más temprana al inicio de la enfermedad, menor edad en el momento de la cirugía inicial y tenían más probabilidades de ser clasificados posteriormente como colitis indeterminada o enfermedad de Crohn. Los pacientes que desarrollaron fístulas perianales también fueron más propensos a desarrollar dehiscencia parcial o estenosis de la anastomosis ileoanal.LIMITACIONES:Este estudio abarca casi 40 años durante los cuales ha evolucionado el procedimiento quirúrgico.CONCLUSIONES:Edad temprana al inicio de la enfermedad, menor edad al momento de la cirugía, diagnóstico postoperatorio de enfermedad de Crohn y colitis indeterminada fueron los factores que se correlacionaron con las fístulas perianales. El retraso en la cicatrización de la anastomosis ileoanal con separación parcial y/o estenosis también se correlacionó con la aparición de fístulas perianales. La gravedad de la inflamación rectal en el momento de la cirugía o la presencia de anastomosis con grapas versus anastomosis manual no se correlacionó con el desarrollo de fístulas perianales. Consulte Video Resumen en http://links.lww.com/DCR/B705.

The p.Ser64Leu and p.Pro104Leu missense variants of PALB2 identified in familial pancreatic cancer patients compromise the DNA damage response.

PALB2 has been identified as a breast and pancreatic cancer susceptibility gene. Utilizing a targeted sequencing approach, we discovered two novel germline missense PALB2 variants c.191C>T and c.311C>T, encoding p.Ser64Leu and p.Pro104Leu, respectively, in individuals in a pancreatic cancer registry. No missense PALB2 variants from familial pancreatic cancer patients, and few PALB2 variants overall, have been functionally characterized. Given the known role of PALB2, we tested the impact of p.Ser64Leu and p.Pro104Leu variants on DNA damage responses. Neither p.Ser64Leu nor p.Pro104Leu have clear effects on interactions with BRCA1 and KEAP1, which are mediated by adjacent motifs in PALB2. However, both variants are associated with defective recruitment of PALB2, and the RAD51 recombinase downstream, to DNA damage foci. Furthermore, p.Ser64Leu and p.Pro104Leu both largely compromise DNA double-strand break-initiated homologous recombination, and confer increased cellular sensitivity to ionizing radiation (IR) and the poly (ADP-ribose) polymerase (PARP) inhibitor Olaparib. Taken together, our results represent the first demonstration of functionally deleterious PALB2 missense variants associated with familial pancreatic cancer and of deleterious variants in the N-terminus outside of the coiled-coil domain. Furthermore, our results suggest the possibility of personalized treatments, using IR or PARP inhibitor, of pancreatic and other cancers that carry a deleterious PALB2 variant.

Incorporating multiple sets of eQTL weights into gene-by-environment interaction analysis identifies novel susceptibility loci for pancreatic cancer.

It is of great scientific interest to identify interactions between genetic variants and environmental exposures that may modify the risk of complex diseases. However, larger sample sizes are usually required to detect gene-by-environment interaction (G × E) than required to detect genetic main association effects. To boost the statistical power and improve the understanding of the underlying molecular mechanisms, we incorporate functional genomics information, specifically, expression quantitative trait loci (eQTLs), into a data-adaptive G × E test, called aGEw. This test adaptively chooses the best eQTL weights from multiple tissues and provides an extra layer of weighting at the genetic variant level. Extensive simulations show that the aGEw test can control the Type 1 error rate, and the power is resilient to the inclusion of neutral variants and noninformative external weights. We applied the proposed aGEw test to the Pancreatic Cancer Case-Control Consortium (discovery cohort of 3,585 cases and 3,482 controls) and the PanScan II genome-wide association study data (replication cohort of 2,021 cases and 2,105 controls) with smoking as the exposure of interest. Two novel putative smoking-related pancreatic cancer susceptibility genes, TRIP10 and KDM3A, were identified. The aGEw test is implemented in an R package aGE.

A pooled genome-wide association study identifies pancreatic cancer susceptibility loci on chromosome 19p12 and 19p13.3 in the full-Jewish population.

Jews are estimated to be at increased risk of pancreatic cancer compared to non-Jews, but their observed 50-80% excess risk is not explained by known non-genetic or genetic risk factors. We conducted a GWAS in a case-control sample of American Jews, largely Ashkenazi, including 406 pancreatic cancer patients and 2332 controls, identified in the dbGaP, PanScan I/II, PanC4 and GERA data sets. We then examined resulting SNPs with P < 10-7 in an expanded sample set, of 539 full- or part-Jewish pancreatic cancer patients and 4117 full- or part-Jewish controls from the same data sets. Jewish ancestries were genetically determined using seeded FastPCA. Among the full Jews, a novel genome-wide significant association was detected on chromosome 19p12 (rs66562280, per-allele OR = 1.55, 95% CI = 1.33-1.81, P = 10-7.6). A suggestive relatively independent association was detected on chromosome 19p13.3 (rs2656937, OR = 1.53, 95% CI = 1.31-1.78, P = 10-7.0). Similar associations were seen for these SNPs among the full and part Jews combined. This is the first GWAS conducted for pancreatic cancer in the increased-risk Jewish population. The SNPs rs66562280 and rs2656937 are located in introns of ZNF100-like and ARRDC5, respectively, and are known to alter regulatory motifs of genes that play integral roles in pancreatic carcinogenesis.

Brain MRI Deep Learning and Bayesian Inference System Augments Radiology Resident Performance.

Automated quantitative and probabilistic medical image analysis has the potential to improve the accuracy and efficiency of the radiology workflow. We sought to determine whether AI systems for brain MRI diagnosis could be used as a clinical decision support tool to augment radiologist performance. We utilized previously developed AI systems that combine convolutional neural networks and expert-derived Bayesian networks to distinguish among 50 diagnostic entities on multimodal brain MRIs. We tested whether these systems could augment radiologist performance through an interactive clinical decision support tool known as Adaptive Radiology Interpretation and Education System (ARIES) in 194 test cases. Four radiology residents and three academic neuroradiologists viewed half of the cases unassisted and half with the results of the AI system displayed on ARIES. Diagnostic accuracy of radiologists for top diagnosis (TDx) and top three differential diagnosis (T3DDx) was compared with and without ARIES. Radiology resident performance was significantly better with ARIES for both TDx (55% vs 30%; P < .001) and T3DDx (79% vs 52%; P = 0.002), with the largest improvement for rare diseases (39% increase for T3DDx; P < 0.001). There was no significant difference between attending performance with and without ARIES for TDx (72% vs 69%; P = 0.48) or T3DDx (86% vs 89%; P = 0.39). These findings suggest that a hybrid deep learning and Bayesian inference clinical decision support system has the potential to augment diagnostic accuracy of non-specialists to approach the level of subspecialists for a large array of diseases on brain MRI.

Education and gastric cancer risk-An individual participant data meta-analysis in the StoP project consortium.

Low socioeconomic position (SEP) is a strong risk factor for incidence and premature mortality from several cancers. Our study aimed at quantifying the association between SEP and gastric cancer (GC) risk through an individual participant data meta-analysis within the "Stomach cancer Pooling (StoP) Project". Educational level and household income were used as proxies for the SEP. We estimated pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) across levels of education and household income by pooling study-specific ORs through random-effects meta-analytic models. The relative index of inequality (RII) was also computed. A total of 9,773 GC cases and 24,373 controls from 25 studies from Europe, Asia and America were included. The pooled OR for the highest compared to the lowest level of education was 0.60 (95% CI, 0.44-0.84), while the pooled RII was 0.45 (95% CI, 0.29-0.69). A strong inverse association was observed both for noncardia (OR 0.39, 95% CI, 0.22-0.70) and cardia GC (OR 0.47, 95% CI, 0.22-0.99). The relation was stronger among H. pylori negative subjects (RII 0.14, 95% CI, 0.04-0.48) as compared to H. pylori positive ones (RII 0.29, 95% CI, 0.10-0.84), in the absence of a significant interaction (p = 0.28). The highest household income category showed a pooled OR of 0.65 (95% CI, 0.48-0.89), while the corresponding RII was 0.40 (95% CI, 0.22-0.72). Our collaborative pooled-analysis showed a strong inverse relationship between SEP indicators and GC risk. Our data call for public health interventions to reduce GC risk among the more vulnerable groups of the population.

Meat intake and risk of gastric cancer in the Stomach cancer Pooling (StoP) project.

The consumption of processed meat has been associated with noncardia gastric cancer, but evidence regarding a possible role of red meat is more limited. Our study aims to quantify the association between meat consumption, namely white, red and processed meat, and the risk of gastric cancer, through individual participant data meta-analysis of studies participating in the "Stomach cancer Pooling (StoP) Project". Data from 22 studies, including 11,443 cases and 28,029 controls, were used. Study-specific odds ratios (ORs) were pooled through a two-stage approach based on random-effects models. An exposure-response relationship was modeled, using one and two-order fractional polynomials, to evaluate the possible nonlinear association between meat intake and gastric cancer. An increased risk of gastric cancer was observed for the consumption of all types of meat (highest vs. lowest tertile), which was statistically significant for red (OR: 1.24; 95% CI: 1.00-1.53), processed (OR: 1.23; 95% CI: 1.06-1.43) and total meat (OR: 1.30; 95% CI: 1.09-1.55). Exposure-response analyses showed an increasing risk of gastric cancer with increasing consumption of both processed and red meat, with the highest OR being observed for an intake of 150 g/day of red meat (OR: 1.85; 95% CI: 1.56-2.20). This work provides robust evidence on the relation between the consumption of different types of meat and gastric cancer. Adherence to dietary recommendations to reduce meat consumption may contribute to a reduction in the burden of gastric cancer.

Fruits and vegetables intake and gastric cancer risk: A pooled analysis within the Stomach cancer Pooling Project.

A low intake of fruits and vegetables is a risk factor for gastric cancer, although there is uncertainty regarding the magnitude of the associations. In our study, the relationship between fruits and vegetables intake and gastric cancer was assessed, complementing a previous work on the association betweenconsumption of citrus fruits and gastric cancer. Data from 25 studies (8456 cases and 21 133 controls) with information on fruits and/or vegetables intake were used. A two-stage approach based on random-effects models was used to pool study-specific adjusted (sex, age and the main known risk factors for gastric cancer) odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Exposure-response relations, including linear and nonlinear associations, were modeled using one- and two-order fractional polynomials. Gastric cancer risk was lower for a higher intake of fruits (OR: 0.76, 95% CI: 0.64-0.90), noncitrus fruits (OR: 0.86, 95% CI: 0.73-1.02), vegetables (OR: 0.68, 95% CI: 0.56-0.84), and fruits and vegetables (OR: 0.61, 95% CI: 0.49-0.75); results were consistent across sociodemographic and lifestyles categories, as well as study characteristics. Exposure-response analyses showed an increasingly protective effect of portions/day of fruits (OR: 0.64, 95% CI: 0.57-0.73 for six portions), noncitrus fruits (OR: 0.71, 95% CI: 0.61-0.83 for six portions) and vegetables (OR: 0.51, 95% CI: 0.43-0.60 for 10 portions). A protective effect of all fruits, noncitrus fruits and vegetables was confirmed, supporting further dietary recommendations to decrease the burden of gastric cancer.

Bayesian copy number detection and association in large-scale studies.

BACKGROUND: Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging due to biological and technical sources of heterogeneity that vary across the genome within and between samples. METHODS: We developed an approach called CNPBayes to identify latent batch effects in genome-wide association studies involving copy number, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. RESULTS: Applying a hidden Markov model (HMM) to identify CNVs in a large multi-site Pancreatic Cancer Case Control study (PanC4) of 7598 participants, we found CNV inference was highly sensitive to technical noise that varied appreciably among participants. Applying CNPBayes to this dataset, we found that the major sources of technical variation were linked to sample processing by the centralized laboratory and not the individual study sites. Modeling the latent batch effects at each CNV region hierarchically, we developed probabilistic estimates of copy number that were directly incorporated in a Bayesian regression model for pancreatic cancer risk. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Suppressor Candidate 3 (TUSC3). CONCLUSIONS: Laboratory effects may not account for the major sources of technical variation in genome-wide association studies. This study provides a robust Bayesian inferential framework for identifying latent batch effects, estimating copy number, and evaluating the role of copy number in heritable diseases.

Data-Driven Quantitative Susceptibility Mapping Using Loss Adaptive Dipole Inversion (LADI).

BACKGROUND: Quantitative susceptibility mapping (QSM) uses prior information to reconstruct maps, but prior information may not show pathology and introduce inconsistencies with susceptibility maps, degrade image quality and inadvertently smoothing image features. PURPOSE: To develop a local field data-driven QSM reconstruction that does not depend on spatial edge prior information. STUDY TYPE: Retrospective. SUBJECTS, ANIMAL MODELS: A dataset from 2016 ISMRM QSM Challenge, 11 patients with glioblastoma, a patient with microbleeds and porcine heart. SEQUENCE/FIELD STRENGTH: 3D gradient echo sequence on 3T and 7T scanners. ASSESSMENT: Accuracy was compared to Calculation of Susceptibility through Multiple Orientation Sampling (COSMOS), and several published techniques using region of interest (ROI) measurements, root-mean-squared error (RMSE), structural similarity index metric (SSIM), and high-frequency error norm (HFEN). Numerical ranking and semiquantitative image grading was performed by three expert observers to assess overall image quality (IQ) and image sharpness (IS). STATISTICAL TESTS: Bland-Altman, Friedman test, and Conover multiple comparisons. RESULTS: Loss adaptive dipole inversion (LADI) (ß = 0.82, R2 = 0.96), morphology-enabled dipole inversion (MEDI) (ß = 0.91, R2 = 0.97), and fast nonlinear susceptibility inversion (FANSI) (ß = 0.81, R2 = 0.98) had excellent correlation with COSMOS and no bias was detected (bias = 0.006 ± 0.014, P < 0.05). In glioblastoma patients, LADI showed consistently better performance (IQGrade = 2.6 ± 0.4, ISGrade = 2.6 ± 0.3, IQRank = 3.5 ± 0.4, ISRank = 3.9 ± 0.2) compared with MEDI (IQGrade = 2.1 ± 0.3, ISGrade = 2 ± 0.5, IQRank = 2.4 ± 0.5, ISRank = 2.8 ± 0.2) and FANSI (IQGrade = 2.2 ± 0.5, ISGrade = 2 ± 0.4, IQRank = 2.8 ± 0.3, ISRank = 2.1 ± 0.2). Dark artifact visible near the infarcted region in MEDI (InfMEDI = -0.27 ± 0.06 ppm) was better mitigated by FANSI (InfFANSI-TGV = -0.17 ± 0.05 ppm) and LADI (InfLADI = -0.18 ± 0.05 ppm). CONCLUSION: For neuroimaging applications, LADI preserved image sharpness and fine features in glioblastoma and microbleed patients. LADI performed better at mitigating artifacts in cardiac QSM. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;52:823-835.

Citrus fruit intake and gastric cancer: The stomach cancer pooling (StoP) project consortium.

Diets rich in vegetables and fruit have been associated with reduced risk of gastric cancer, and there is suggestive evidence that citrus fruits have a protective role. Our study aimed at evaluating and quantifying the association between citrus fruit intake and gastric cancer risk. We conducted a one-stage pooled analysis including 6,340 cases and 14,490 controls from 15 case-control studies from the stomach cancer pooling (StoP) project consortium. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of gastric cancer across study-specific tertiles of citrus fruit intake (grams/week) were estimated by generalized linear mixed effect models, with logistic link function and random intercept for each study. The models were adjusted for sex, age, and the main recognized risk factors for gastric cancer. Compared to the first third of the distribution, the adjusted pooled OR (95% CI) for the highest third was 0.80 (0.73-0.87). The favourable effect of citrus fruits increased progressively until three servings/week and leveled off thereafter. The magnitude of the association was similar between cancer sub-sites and histotypes. The analysis by geographic area showed no association in studies from the Americas. Our data confirm an inverse association between citrus fruits and gastric cancer and provide precise estimates of the magnitude of the association. However, the null association found in studies from America and in some previous cohort studies prevent to draw definite conclusions on a protective effect of citrus fruit consumption.

Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues.

OBJECTIVE: To elucidate the genetic architecture of gene expression in pancreatic tissues. DESIGN: We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison. RESULTS: We identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant cis-eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8×10-8) and tumour-derived (p=8.3×10-5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the 'O' mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO 'O' mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL. CONCLUSIONS: We have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.

Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P = 2.30 × 10-11, OR = 1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r2 = 0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (ß = 0.26, P = 0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ∼6 kb upstream of DIS3 Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.

Alcohol consumption and gastric cancer risk-A pooled analysis within the StoP project consortium.

An association between heavy alcohol drinking and gastric cancer risk has been recently reported, but the issue is still open to discussion and quantification. We investigated the role of alcohol drinking on gastric cancer risk in the "Stomach cancer Pooling (StoP) Project," a consortium of epidemiological studies. A total of 9,669 cases and 25,336 controls from 20 studies from Europe, Asia and North America were included. We estimated summary odds-ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study-specific ORs using random-effects meta-regression models. Compared with abstainers, drinkers of up to 4 drinks/day of alcohol had no increase in gastric cancer risk, while the ORs were 1.26 (95% CI, 1.08-1.48) for heavy (>4 to 6 drinks/day) and 1.48 (95% CI 1.29-1.70) for very heavy (>6 drinks/day) drinkers. The risk for drinkers of >4 drinks/day was higher in never smokers (OR 1.87, 95% CI 1.35-2.58) as compared with current smokers (OR 1.14, 95% CI 0.93-1.40). Somewhat stronger associations emerged with heavy drinking in cardia (OR 1.61, 95% CI 1.11-2.34) than in non-cardia (OR 1.28, 95% CI 1.13-1.45) gastric cancers, and in intestinal-type (OR 1.54, 95% CI 1.20-1.97) than in diffuse-type (OR 1.29, 95% CI 1.05-1.58) cancers. The association was similar in strata of H. pylori infected (OR = 1.52, 95% CI 1.16-2.00) and noninfected subjects (OR = 1.69, 95% CI 0.95-3.01). Our collaborative pooled-analysis provides definite, more precise quantitative evidence than previously available of an association between heavy alcohol drinking and gastric cancer risk.

The oral microbiota in patients with pancreatic cancer, patients with IPMNs, and controls: a pilot study.

PURPOSE: Poor oral health appears to be a risk factor for pancreatic cancer, possibly implicating the oral microbiota. In this pilot study, we evaluated the characteristics of the oral microbiota in patients with pancreatic ductal adenocarcinoma (PDAC), intraductal papillary mucinous neoplasms (IPMN), and healthy controls. METHODS: Forty newly diagnosed PDAC patients, 39 IPMN patients, and 58 controls, excluding current smokers and users of antibiotics, provided saliva samples. Common oral bacterial species were comprehensively surveyed by sequencing of the 16S rRNA microbial genes. We obtained measures of diversity and the mean relative proportions of individual taxa. We explored the degree to which these measures differed according to respondent characteristics based on individual interviews. RESULTS: PDAC cases did not differ in diversity measures from either controls or IPMN cases. PDAC cases had higher mean relative proportions of Firmicutes and related taxa, while controls had higher mean relative proportions of Proteobacteria and related taxa. Results were generally similar when comparing PDAC to IPMN cases. Among IPMNs and controls combined, younger individuals had higher levels of several taxa within the Proteobacteria. The only other variable consistently related to mean relative proportions was mouthwash use, with taxa within Firmicutes more common among users. CONCLUSIONS: While there were no differences in diversity of the oral microbiota among these groups, there were differences in the mean relative proportions of some taxa. Characteristics of the oral microbiota are not associated with most measures of oral health.

Identification of germline genetic mutations in patients with pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC. METHODS: A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated. RESULTS: Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age ≤ 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation). CONCLUSIONS: Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation.

A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma.

BACKGROUND: The role for neoadjuvant systemic therapy in resectable pancreas adenocarcinoma remains undefined. OBJECTIVE: We evaluated the efficacy of gemcitabine and oxaliplatin administered as preoperative therapy in patients with resectable pancreas adenocarcinoma. METHODS: Eligible patients were screened using computed tomography-pancreas angiography, laparoscopy, endoscopic ultrasonography, and fine-needle aspiration cytology to identify 38 patients who received 4 cycles of neoadjuvant gemcitabine 1000 mg/m intravenously over 100 minutes and oxaliplatin 80 mg/m intravenously over 2 hours, every 2 weeks. Patients whose tumors remained resectable at restaging proceeded to operation and subsequently received 5 cycles of adjuvant gemcitabine (1000 mg/m intravenously over 30 minutes days 1, 8, and 15 every 4 weeks). The primary endpoint was 18-month overall survival and secondary endpoints included radiological, tumor marker and pathological response to neoadjuvant therapy, time to recurrence, patterns of failure, and feasibility of obtaining preoperative core biopsies. RESULTS: Thirty-five of 38 patients (92%) completed neoadjuvant therapy. Twenty-seven patients underwent tumor resection (resectability rate 71%), of which 26 initiated adjuvant therapy for a total of 23 patients (60.5%) who completed all planned therapy. The 18-month survival was 63% (24 patients alive). The median overall survival for all 38 patients was 27.2 months (95% confidence interval: 17-NA) and the median disease-specific survival was 30.6 months (95% confidence interval: 19-NA). CONCLUSIONS: This study met its endpoint and provided a signal suggesting that exploration of neoadjuvant systemic therapy is worthy of further investigation in resectable pancreas adenocarcinoma. Improved patient selection and more active systemic regimens are key. Clinical trials identification: NCT00536874.