scholarly journals Genetic Alterations Featuring Biological Models to Tailor Clinical Management of Pancreatic Cancer Patients

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1233 ◽  
Author(s):  
Shannon R. Nelson ◽  
Naomi Walsh
Keyword(s):  
Pancreatic Cancer ◽  
Association Studies ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Ductal Adenocarcinoma ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Primary Cell Lines ◽  
On Chip ◽  
New Research

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide. This high mortality rate is due to the disease’s lack of symptoms, resulting in a late diagnosis. Biomarkers and treatment options for pancreatic cancer are also limited. In order to overcome this, new research models and novel approaches to discovering PDAC biomarkers are required. In this review, we outline the hereditary and somatic causes of PDAC and provide an overview of the recent genome wide association studies (GWAS) and pathway analysis studies. We also provide a summary of some of the systems used to study PDAC, including established and primary cell lines, patient-derived xenografts (PDX), and newer models such as organoids and organ-on-chip. These ex vitro laboratory systems allow for critical research into the development and progression of PDAC.

scholarly journals Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer

2017 ◽  
Author(s):  
Knut M. Wittkowski ◽  
Christina Dadurian ◽  
Martin P. Seybold ◽  
Han Sang Kim ◽  
Ayuko Hoshino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Animal Studies ◽  
Association Studies ◽  
Treatment Options ◽  
Cell Cycle Control ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Estrogen Receptor Positive

AbstractMost breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600–2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance.Results from three independent GWAS of 1000–2000 subjects each, which were made available under the National Institute of Health’s “Up For A Challenge” (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids via alpha-cyclodextrins (αCD) as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of β1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells).Beta-cyclodextrins (βCD) have already been shown to be effective inin vitroand animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller αCDs also scavenges phospholipids, but cannot fit cholesterol. Anin-vitrostudy presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPβCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer.If the previous successful animal studies with βCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triplenegative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

scholarly journals Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

2020 ◽  
pp. jmedgenet-2020-106961 ◽  
Author(s):  
Alice Alessandra Galeotti ◽  
Manuel Gentiluomo ◽  
Cosmeri Rizzato ◽  
Ofure Obazee ◽  
John P Neoptolemos ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Risk Prediction ◽  
Association Studies ◽  
Statistical Significance ◽  
Ductal Adenocarcinoma ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Individual Snps ◽  
Risk Snps

BackgroundMost cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.ObjectiveWe generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.MethodsWe tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.ResultsThe scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).ConclusionWe found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

Novel pancreatic cancer susceptibility loci discovered through genome-wide association studies

Pancreatology ◽  
2015 ◽  
Vol 15 (3) ◽  
pp. S49
Author(s):  
Federico Canzian ◽  
Daniele Campa ◽  
Cosmeri Rizzato ◽  
Maarten F. Bijlsma ◽  
Hermann Brenner ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Genome Wide

scholarly journals Genetic risk factors for eating disorders: an update and insights into pathophysiology

2019 ◽  
Vol 9 ◽  
pp. 204512531881473 ◽  
Author(s):  
Hubertus Himmerich ◽  
Jessica Bentley ◽  
Carol Kan ◽  
Janet Treasure
Keyword(s):  
Eating Disorders ◽  
Association Studies ◽  
Treatment Options ◽  
Genetic Research ◽  
Endocrine System ◽  
Gene Interaction ◽  
Historical Background ◽  
Genome Wide Association Studies ◽  
Candidate Gene Association ◽  
Genome Wide

Genome-wide-association studies (GWASs), epigenetic, gene-expression and gene–gene interaction projects, nutritional genomics and investigations of the gut microbiota have increased our knowledge of the pathophysiology of eating disorders (EDs). However, compared with anorexia nervosa, genetic studies in patients with bulimia nervosa and binge-eating disorder are relatively scarce, with the exception of a few formal genetic and small-sized candidate–gene-association studies. In this article, we review important findings derived from formal and molecular genetics in order to outline a genetics-based pathophysiological model of EDs. This model takes into account environmental and nutritional factors, genetic factors related to the microbiome, the metabolic and endocrine system, the immune system, and the brain, in addition to phenotypical traits of EDs. Shortcomings and advantages of genetic research in EDs are discussed against the historical background, but also in light of potential future treatment options for patients with EDs.

Novel pancreatic cancer susceptibility loci discovered through genome-wide association studies

Pancreatology ◽  
2018 ◽  
Vol 18 (4) ◽  
pp. S8
Author(s):  
Federico Canzian ◽  
Daniele Campa ◽  
Ofure Obazee ◽  
Cosmeri Rizzato ◽  
Maria Gazouli ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Genome Wide

scholarly journals Bayesian copy number detection and association in large-scale studies

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Stephen Cristiano ◽  
David McKean ◽  
Jacob Carey ◽  
Paige Bracci ◽  
Paul Brennan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Copy Number ◽  
Large Scale ◽  
Association Studies ◽  
Regulatory Elements ◽  
Bayesian Regression ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Batch Effects ◽  
Genome Wide

Abstract 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.

scholarly journals A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

2020 ◽  
Vol 112 (10) ◽  
pp. 1003-1012 ◽  
Author(s):  
Jun Zhong ◽  
Ashley Jermusyk ◽  
Lang Wu ◽  
Jason W Hoskins ◽  
Irene Collins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Cancer Risk ◽  
Association Study ◽  
Association Studies ◽  
Tissue Expression ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Pancreatic Cancer Risk ◽  
Genome Wide

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

scholarly journals Pharmacogenomic study of side-effects for antidepressant treatment options in STAR*D

2011 ◽  
Vol 42 (6) ◽  
pp. 1151-1162 ◽  
Author(s):  
S. L. Clark ◽  
D. E. Adkins ◽  
K. Aberg ◽  
J. M. Hettema ◽  
J. L. McClay ◽  
...  
Keyword(s):  
Side Effects ◽  
Antidepressant Treatment ◽  
Association Studies ◽  
Treatment Options ◽  
Antidepressant Medication ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Sexual Side Effects ◽  
Genome Wide ◽  
Treatment Of Depression

BackgroundUnderstanding individual differences in susceptibility to antidepressant therapy side-effects is essential to optimize the treatment of depression.MethodWe performed genome-wide association studies (GWAS) to search for genetic variation affecting the susceptibility to side-effects. The analysis sample consisted of 1439 depression patients, successfully genotyped for 421K single nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Outcomes included four indicators of side-effects: general side-effect burden, sexual side-effects, dizziness and vision/hearing-related side-effects. Our criterion for genome-wide significance was a prespecified threshold ensuring that, on average, only 10% of the significant findings are false discoveries.ResultsThirty-four SNPs satisfied this criterion. The top finding indicated that 10 SNPs inSACM1Lmediated the effects of bupropion on sexual side-effects (p=4.98×10−7,q=0.023). Suggestive findings were also found for SNPs inMAGI2,DTWD1,WDFY4andCHL1.ConclusionsAlthough our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that could mediate adverse effects of antidepressant medication.

scholarly journals Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population

2018 ◽  
Author(s):  
Yingsong Lin ◽  
Masahiro Nakatochi ◽  
Hidemi Ito ◽  
Yoichiro Kamatani ◽  
Akihito Inoko ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Japanese Population ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Meta Analysis ◽  
Functional Characterization ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Gene Variants ◽  
Genome Wide

AbstractThe etiology of pancreatic cancer remains largely unknown. Here, we report the results of a meta-analysis of three genome-wide association studies (GWASs) comprising 2,039 pancreatic cancer cases and 32,592 controls, the largest sample size in the Japanese population. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P<5.0×10-8) and 4 suggestive loci (P<1.0×10-6) for pancreatic cancer. Of these risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (odds ratio (OR)=1.46, 95% CI=1.29-1.66, P=4.28×10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant predicted to be highly deleterious. Additionally, the gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified GP2 gene variants were pleiotropic for multiple traits, including type 2 diabetes, hemoglobin A1c (HbA1c) levels, and pancreatic cancer. Mendelian randomization analyses corroborated causality between HbA1c and pancreatic cancer. These findings suggest that GP2 gene variants are associated with pancreatic cancer susceptibility in the Japanese population, prompting further functional characterization of this locus.

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