Citations

Abstract Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case–control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10−8 in the meta-analysis; Pinteraction = 2.1 × 10−9 in the case–control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

Abstract Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

Abstract Introduction: Pancreatic cancer is the seventh leading cause of cancer death worldwide with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype (>90%). Inherited genetic changes and cigarette smoking are established independent risk factors of PDAC. Methods: We conducted a genome-wide gene by smoking interaction analysis of PDAC risk among 7,937 PDAC cases and 12,389 controls of European ancestry from the Pancreatic Cancer Cohort (PanScan) and Pancreatic Cancer Case-Control Consortia (PanC4) with complete genotyping and smoking data. Over 6,769,447 SNPs met our inclusion criteria of imputation score >0.5 and MAF >0.05 after imputation to phase 3 1000G and were included in our analysis. We evaluated the gene-environment interactions using the empirical Bayes method which allows data-adaptive relaxation of the gene-environment independence assumption. The logistic regression model was adjusted for age, sex, top principal components for each phase, study and study region (PanScan only). The analysis was conducted separately for the PanScan and PanC4 GWAS studies, using a score test to efficiently incorporate expected SNP dosages. The estimates were then combined using a fixed-effect meta-analysis. We examined expression quantitative trait locus using data from the NIH Genotype-Tissue Expression (GTEx) database. We considered a P-value < 5.0 × 10−8 statistically significant. Results: We found a genome-wide significant qualitative interaction with the SNP rs1818613 by smoking status (P-value <5 × 10−9) where, compared to the G allele, the T allele was associated with a reduced risk PDAC in never smokers (per T allele OR, 0.87; 95% CI, 0.82-0.93), had no association in former smokers (OR, 1.00; 95% CI, 0.91-1.07) and was associated with an increased risk in current smokers (OR, 1.25; 95% CI, 1.12-1.40). This SNP is located on chromosome 2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) gene and upstream of the cyclin T2 (CCNT2) gene. More than 40 additional SNPs within 100Kbp and in high LD (r2 > 0.8) with rs1818613 provided significant evidence of interaction by smoking status for PDAC risk. rs1818613 was associated with differential expression of TMEM163 in several tissues: for T allele compared with the G allele there was increased expression in the heart, pituitary, whole blood, and esophagus-muscularis and decreased expression in the testis tissues (P-value < 3 × 10−11). It was also associated with decreased CCNT2 expression in the tibial nerve tissue (P-value = 1.9 × 10−9). Conclusions: Our work supports that the genetic variation in the region, in conjunction with cigarette smoking, influences PDAC risk. Future studies are needed to explore this association in other smoking-related cancers and to understand the biological mechanism of such association. Citation Format: Prosenjit Kundu, Evelina Mocci, William Wheeler, Laufey T. Amundadottir, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Peter Kraft, Nilanjan Chatterjee, Alison P. Klein, Rachael Z. Stolzenberg-Solomon, The PanScan and Panc4 consortia. Genome-wide interaction scan identifies gene by smoking interaction at 2q21.3 for pancreatic cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1213.

Abstract Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10−6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. Significance: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.

BACKGROUND: An increasing proportion of pediatric hospital days are attributed to technology-dependent children. The impact that a pediatric home care nursing (HCN) shortage has on increasing length of hospital stay and readmissions in this population is not well documented. METHODS: We conducted a 12-month multisite prospective study of children with medical complexity discharging with home health. We studied the following 2 cohorts: new patients discharging for the first time to home nursing and existing patients discharging from the hospital to previously established home nursing. A modified delay tool was used to categorize causes, delayed discharge (DD) days, and unplanned 90-day readmissions. RESULTS: DD occurred in 68.5% of 54 new patients and 9.2% of 131 existing patients. Lack of HCN was the most frequent cause of DD, increasing costs and directly accounting for an average length of stay increase of 53.9 days (range: 4–204) and 35.7 days (3–63) for new and existing patients, respectively. Of 1582 DDs, 1454 (91.9%) were directly attributed to lack of HCN availability. DD was associated with younger age and tracheostomy. Unplanned 90-day readmissions were due to medical setbacks (96.7% of cases) and occurred in 53.7% and 45.0% of new and existing patients, respectively. CONCLUSIONS: DD and related costs are primarily associated with shortage of HCN and predominantly affect patients new to HCN. Medical setbacks are the most common causes of unplanned 90-day readmissions. Increasing the availability of home care nurses or postacute care facilities could reduce costly hospital length of stay.

Cell therapy is an emerging form of treatment for several liver diseases, but is limited by the availability of donor livers. Stem cells hold promise as an alternative to the use of primary hepatocytes. We performed an exhaustive review of the literature, with a focus on the latest studies involving the use of stem cells for the treatment of liver disease. Stem cells can be harvested from a number of sources, or can be generated from somatic cells to create induced pluripotent stem cells (iPSCs). Different cell lines have been used experimentally to support liver function and treat inherited metabolic disorders, acute liver failure, cirrhosis, liver cancer, and small-for-size liver transplantations. Cell-based therapeutics may involve gene therapy, cell transplantation, bioartificial liver devices, or bioengineered organs. Research in this field is still very active. Stem cell therapy may, in the future, be used as a bridge to either liver transplantation or endogenous liver regeneration, but efficient differentiation and production protocols must be developed and safety must be demonstrated before it can be applied to clinical practice.