The incidence of early-onset colorectal cancer, defined as colorectal cancer occurring in young adults under the age of 50, is increasing globally. Knowledge of the etiological factors in young ...adults is far from complete. Questionable eoCRCs’ exogenous factors are represented by processed meat, sugary drinks, alcohol, Western dietary pattern, overweight and obesity, physical inactivity, and smoking, though with heterogeneous results. Therefore, we performed a systematic review to summarize the current evidence on the role of diet and lifestyle as eoCRC risk factors. We systematically searched PubMed, Scopus, and EMBASE up to July 2021, for original studies evaluating diet, alcohol, physical activity, BMI, and smoking in eoCRC and included twenty-six studies. Indeed, the exogenous factors could represent modifiable key factors, whose recognition could establish areas of future interventions through public health strategies for eoCRC primary prevention. Additionally, we discussed the role of additional non-modifiable risk factors, and of epigenetic regulation and microbiota as mediators of the eoCRC triggered by diet and lifestyle.
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer‐related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in ...risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome‐wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10−9). This SNP is located in the NONHSAG053086.2 (lnc‐SMC2‐1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro‐RNA (miRNA) hsa‐mir‐1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome‐wide statistical significance and a plausible biological mechanism.
What's new?
Long non‐coding RNAs (lncRNAs) are thought to contribute to cancer development. Here, the authors searched for new lncRNA variants that are associated with risk of pancreatic ductal adenocarcinoma (PDAC). From analysis of 15,000 individuals, they obtained 67 variants associated with PDAC risk. Some of these were located in genes previously associated with PDAC, an outcome which not only validates the method but could shed light on the functional relevance of these genes. The strongest association was to a variant in the lnc‐SMC2‐1 gene, and the risk allele is predicted to disrupt cell cycle regulation.
Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore, we performed a genome‐wide ...association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I‐II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1 × 10−4). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset ≤50, and 4142 controls from the PANDoRA consortium while in the in silico data, we observed no statistically significant association. However, the resulting meta‐analysis supported the association (P = 1.15 × 10−4). In conclusion, we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature.
What's new?
Early‐onset pancreatic cancer (EOPC), diagnosed between ages 45 and 60, accounts for about one‐fifth of all pancreatic cancers. Nonetheless, while multiple epidemiological risk factors for EOPC have been identified, very little is known about genetic susceptibility. The present genome‐wide association study identifies four novel single nucleotide polymorphisms specific for patients diagnosed with pancreatic cancer at younger ages. Among the variants, 13q22.3_rs2328991 was associated with elevated risk in an independent set of pancreatic cancer patients, some of whom experienced disease onset at age 50 or younger. The findings highlight a need for further research on the genetics of EOPC.
Hereditary colorectal cancer syndromes require timely endoscopic surveillance.
This study evaluated the approach of Italian gastroenterologists to the management of such patients. It then assessed ...the impact of SARS-CoV-2. All members affiliated with the leading Italian gastroenterology societies (AIGO, SIED, and SIGE) received an online questionnaire.
One hundred and twenty-one clinicians from 96 centers answered, not necessarily experts in the field (mean age 50.26 ± 11.22 years). Many collected family history for genetic risk assessment (74.4%), but only 14.0% used an online predictive software. 65.6% discussed cases in multidisciplinary units. Genetic analysis was available to most centers, but only a few hospitals offered dedicated endoscopy (19.0%), outpatient clinics (33.9%), or surgeries (23.1%). Since the start of the SARS-CoV-2 pandemic, the number of clinicians with a high volume of patients decreased (from 38.8% to 28.1%). Almost half of the responders (45.5%) reported a delay in the surveillance (median: 4-12 months). Ultimately, 30.6% detected one interval colorectal cancer in at least one of their patients.
The SARS-CoV-2 pandemic directly affected the surveillance of hereditary colorectal cancer syndromes in Italy. Endoscopic surveillance should resume in all centers to avoid the possible long-term consequences of its interruption, especially for inherited colorectal cancer syndromes.
Autoimmune diseases are often associated with human leukocyte antigen (HLA) haplotypes, indicating that changes in major histocompatibility complex (MHC)-dependent self-peptide or antigen ...presentation contribute to autoimmunity. In our study, we aimed to investigate HLA alleles in a large European cohort of autoimmune pancreatitis (AIP) patients.
Hundred patients with AIP, diagnosed and classified according to the International Consensus Diagnostic Criteria (ICDC), were prospectively enrolled in the study. Forty-four patients with chronic pancreatitis (CP) and 254 healthy subjects served as control groups. DNA was isolated from blood samples and two-digit HLA typing was performed with sequence-specific primer (SSP-) PCR. HLA allele association strength to AIP was calculated as odds ratio.
We uncovered a strong enrichment of HLA-DQB1 homozygosity in type 1 and type 2 AIP patients. Moreover, a significantly increased incidence of the HLA-DRB1∗16 and HLA-DQB1∗05 alleles and a concomitant lack of the HLA-DRB1∗13 allele was detected in AIP type 1 and type 2 patients. In contrast, the HLA-DQB1∗02 allele was underrepresented in the ‘not otherwise specified’ (NOS) AIP subtype. We detected no significant difference in the HLA-DRB3, HLA-DRB4 and HLA-DRB5 allele frequency in our cohort.
Although AIP type 1 and type 2 are characterized by distinct histopathological characteristics, both subtypes are associated with the same HLA alleles, indicating that the disease might rely on similar immunogenic mechanisms. However, AIP NOS represented another subclass of AIP.
Acute, acute recurrent, and chronic pancreatitis are inflammatory diseases with multifactorial pathogenic mechanisms. Genetic mutations and polymorphisms have been correlated with pancreatitis. The ...aim of this study was to investigate the association of cystic fibrosis transmembrane conductance regulator (CFTR) and serine protease inhibitor Kazal type 1 (SPINK-1) gene mutations and monocyte chemoattractant protein 1 (MCP-1) -2518A/G polymorphism with acute pancreatitis (AP), acute recurrent pancreatitis (ARP), and chronic pancreatitis (CP), and to associate genetic backgrounds with clinical phenotype in these three conditions.
One hundred eighteen AP, 64 ARP, 142 CP patients, and 88 normal controls were enrolled consecutively. We analyzed MCP-1 serum levels using enzyme-linked immunosorbent assay. Polymorphism -2518 of MCP-1 and SPINK-1 N34S gene mutations were determined by PCR-restriction-fragment length polymorphism. Sequence analysis was performed when necessary. Thirty-three CFTR mutations were analyzed in CP and ARP patients using multiplex DNA testing.
Serum MCP-1 levels were significantly higher in all patients affected by pancreatic inflammatory diseases. Moreover, we found a significant over-representation of the MCP-1G allele in ARP patients. We found a statistically significant association of CFTR gene mutations with ARP, but not with CP. We did not find a statistically significant association of ARP or CP with the N34S SPINK-1 gene mutation. Interestingly, 39 of 64 ARP patients (61%) carried at least one genetic mutation and/or polymorphism. Five of 64 ARP patients had pancreas divisum and four of these five also carried the G allele.
Analysis of a comprehensive range of potential susceptibility variants is needed to support modeling of the effects of genes and environment in pancreatitis. As such, beyond gene mutations, the context within which those mutations exist must be considered. In pancreatitis the context includes the inflammatory response, clinical features, and exogenous factors.
AIM:To assess the rate of relapses of acute pancreatitis(AP),recurrent AP(RAP)and the evolution of endosonographic signs of chronic pancreatitis(CP)in patients with pancreas divisum(PDiv)and ...RAP.METHODS:Over a five-year period,patients with PDiv and RAP prospectively enrolled were divided into two groups:(1)those with relapses of AP in the year before enrollment were assigned to have endoscopic therapy(recent RAP group);and(2)those free of recurrences were conservatively managed,unless they relapsed during follow-up(previous RAP group).All patients in both groups entered a follow-up protocol that includedclinical and biochemical evaluation,pancreatic endoscopic ultrasonography(EUS)every year and after every recurrence of AP,at the same time as endoscopic retrograde cholangiopancreatography(ERCP).RESULTS:Twenty-two were treated by ERCP and 14were conservatively managed during a mean follow-up of 4.5±1.2 years.In the recent RAP group in whom dorsal duct drainage was achieved,AP still recurred in11(57.9%)after the first ERCP,in 6 after the second ERCP(31.6%)and in 5 after the third ERCP(26.3%).Overall,endotherapy was successful 73.7%.There were no cases of recurrences in the previous RAP group.EUS signs of CP developed in 57.9%of treated and 64.3%of untreated patients.EUS signs of CP occurred in 42.8%of patients whose ERCPs were successful and in all those in whom it was unsuccessful(P=0.04).There were no significant differences in the rate of AP recurrences after endotherapy and in the prevalence of EUS signs suggesting CP when comparing patients with dilated and non-dilated dorsal pancreatic ducts within each group.CONCLUSION:Patients with PDiv and recent episodes of AP can benefit from endoscopic therapy.Effective endotherapy may reduce the risk of developing EUS signs of CP at a rate similar to that seen in patients of previous RAP group,managed conservatively.However,in a subset of patients,endotherapy,although successful,did not prevent the evolution of endosonographic signs of CP.
Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts (AGE). ...Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP).
Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples.
In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: p = 0.07, logistic regression: p = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087).
Common GLO1 variants do not increase chronic pancreatitis risk.
Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast to chronic ...pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP.
We screened 1462 AP patients and 3999 controls with melting curve analysis for SNPs rs10273639 (PRSS1-PRSS2), rs7057398 (RIPPLY), and rs12688220 (MORC4). Calculations were performed for the overall group, aetiology, and gender sub-groups. To examine genotype-phenotype relationships we performed several meta-analyses.
Meta-analyses of all AP patients depicted significant (p-value < 0.05) associations for rs10273639 (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.81–0.97, p-value 0.01), rs7057398 (OR 1.27, 95% CI 1.07–1.5, p-value 0.005), and rs12688220 (OR 1.32, 95% CI 1.12–1.56, p-value 0.001). For the different aetiology groups a significant association was shown for rs10273639 (OR 0.76, 95% CI 0.63–0.92, p-value 0.005), rs7057398 (OR 1.43, 95% CI 1.07–1.92, p-value 0.02), and rs12688220 (OR 1.44, 95% CI 1.07–1.93, p-value 0.02) in the alcoholic sub-group only.
The association of CP risk variants with different AP aetiologies, which is strongest in the alcoholic AP group, might implicate common pathomechanisms most likely between alcoholic AP and CP.
Analysis of GPRC6A variants in different pancreatitis etiologies Kaune, Tom; Ruffert, Claudia; Hesselbarth, Nico ...
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... et al.,
October 2020, 2020-10-00, 20201001, 2020-10, Letnik:
20, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to ...increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies.
We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis.
We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65–0.89, p = 8 × 10−5) and a Chinese cohort (OR 0.78, 95% CI 0.64–0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99–1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis.
Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.
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