Genetic polymorphisms involved in mitochondrial metabolism and pancreatic cancer risk

The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC aetiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNPs) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported.We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analysed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using MAGMA software.In the discovery phase we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P <0.05). In the second phase none of the findings were replicated. In the gene-level analysiswe observed that three genes (TERT, SUGCT and SURF1) involved in the mitochondrial metabolismshowed an association below the Bonferroni-corrected threshold of statistical significance (P=0.05/1588=3.1 x10-5).Even though the mitochondrial metabolism might be involved in PDAC aetiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk.This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk

Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10−5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk

Susceptibility loci for pancreatic cancer in genes involved in mitochondrial metabolism.

Il pancreas è un organo che presenta una componente endocrina ed una esocrina da cui possono svilupparsi differenti tumori: dalla parte esocrina insorge l’adenocarcinoma duttale pancratico (PDAC), mentre dalla parte endocrina si sviluppano i tumori neuroendocrini pancreatici (PNET). Il cancro al pancreas è attualmente la settima causa di morte dovuta a tumori nel mondo e la quarta in Europa. I principali fattori di rischio ambientali epidemiologici per lo sviluppo del cancro al pancreas comprendono età, sesso, fumo, etnia, diabete e la pancreatite cronica. Una parte del rischio di sviluppare il cancro al pancreas è associato a mutazioni ad alta penetranza che però sono estremamente rare nella popolazione e quindi spiegano soltanto una piccola frazione dei tumori sporadici pancreatici. Gli Studi di Associazione Genome-Wide (GWAS) hanno identificato 27 varianti comuni, a bassa penetranza, che contribuiscono all‘insorgenza della patologia, tuttavia queste varianti rappresentano soltanto una piccola parte dell’ereditabilità della patologia sottolineando la necessità di identificare nuovi loci di suscettibilità. La maggior parte degli studi sulla di associazione condotti per determinare il coinvolgimento genetico nello sviluppo del PDAC sono stati condotti utilizzando esclusivamente il genoma nucleare. Tuttavia, in diversi studi è stato dimostrato il coinvolgimento di mutazioni mitocondriali e di varianti di geni nucleari coinvolti nel metabolismo mitocondriale nello sviluppo patologie metaboliche, diabete ed obesità, che sono fattori di rischio accertati per il cancro al pancreas. Per questo motivo, lo scopo di questo studio è stato approfondire le nostre conoscenze sulla suscettibilità genetica del PDAC focalizzandoci su varianti di geni nucleari coinvolti nel metabolismo mitocondriale

Big data analysis to discover genetic and environmental pancreatic cancer risk factors.

L'adenocarcinoma duttale pancreatico (PDAC) è una malattia complessa che insorge dall'interazione tra la componente genetica e l’esposizione ambientale. Sebbene la conoscenza sui fattori di rischio del PDAC sia limitata, nessuno studio ha esaminato in modo esaustivo l'esposoma (definito come la misura di tutte le esposizioni ai fattori di rischio) in combinazione con la variabilità genetica in relazione alla suscettibilità della malattia. Comprendere l'epidemiologia del PDAC sarebbe fondamentale per identificarne l'eziologia e mettere a punto una strategia di prevenzione. Questo progetto di dottorato mira ad ampliare le conoscenze sui fattori di rischio genetici e non genetici del PDAC, analizzando la suscettibilità genetica, l’esposoma e l'interazione tra i loci di suscettibilità noti e i fattori ambientali. Per raggiungere gli obiettivi di questo progetto, è stato adottato un approccio multidisciplinare che integra analisi secondarie, metodologie epidemiologiche classiche e approcci di intelligenza artificiale (IA). Le analisi secondarie si basano su ipotesi biologiche postulate a priori. Questo progetto ne indaga due: l'impatto dell'attività ormonale femminile e l'autofagia come potenziali fattori di rischio per il PDAC. I metodi epidemiologici classici (come l'analisi di associazione, il punteggio di rischio poligenico (PRS) e l'interazione gene-ambiente (G×E)), insieme a modelli di IA spiegabili, sono stati utilizzati per identificare nuovi fattori di rischio ambientali per il PDAC, per scoprire l'interazione tra la componente genetica e ambientale e per costruire un modello predittivo del rischio di PDAC. Tutti questi approcci sono stati applicati nel contesto di una delle più grandi coorti prospettiche disponibili ad oggi, UK Biobank. Le analisi secondarie hanno confermato associazioni già note, come quella con il gene NR5A2 (p=4.08×10-5) considerando solo le donne con PDAC, ma anche quella con i geni TP53 (p=2.50×10-4) e TP63 (p=8.43×10-9) e il rischio di PDAC. Per quanto riguarda la suscettibilità ambientale, è stato osservato un totale di 147 associazioni a p<0.05 e 54 sotto la soglia di significatività ottenuta con la correzione di Bonferroni di p<1.37×10-4. I nostri risultati sottolineano l'importanza dello stress e dei comportamenti sedentari nella suscettibilità del PDAC, suggerendo che cambiamenti nello stile di vita potrebbero essere utili per ridurre il rischio della malattia. Infine, abbiamo integrato la componente genetica con quella ambientale per sviluppare un modello predittivo per il PDAC che ha ottenuto delle buone performance (accuratezza complessiva di CatBoost=85,24% e recall sui casi=77,10%). Il nostro studio ha confermato alcuni fattori genetici e scoperto nuovi fattori ambientali associati al rischio di sviluppare PDAC, fondamentali per sviluppare un futuro screening sui soggetti ad alto rischio. Inoltre, abbiamo calcolato un modello predittivo per la valutazione del rischio di PDAC, che potrebbe essere utilizzato come strumento di screening su una popolazione più ampia

Supplementary Figures 1_4

Figures (1_4) of the MR analyses conducted to assess the causal role of physical activity and sedentary behaviours on pancreatic cancer risk. The study's results show the causal role of the time spent watching television on the risk of developing pancreatic cancer.</p

Supplementary table 1. List of selected SNP included in the MR analyses.

List of the variants selected to perform the mendelian randomization analyses.SE Standard Error. MVPA Moderate to vigorous physical activity; OaD Overall activity (identified by Doherty et al (35)); OaK Overall activity (identified by Klimentidis et al(32)); VpaK Vigorous physical activity; SbD Sedentary behaviour (identified by Doherty et al(35)); Srcu Self-reported computer use; Srdt Self-reported driving time; SrSbw Self-reported Sedentary behaviour at work (identified by Wang et al(34)); SrTVu Self-reported TV use.</p

Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10−5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk

Genetic polymorphisms involved in mitochondrial metabolism and pancreatic cancer risk.

BackgroundThe mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC aetiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNPs) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported.MethodsWe conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analysed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using MAGMA software.ResultsIn the discovery phase we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P ConclusionsEven though the mitochondrial metabolism might be involved in PDAC aetiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk.ImpactThis large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk

Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P &lt; 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 - 3.1 x 10(-5)). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk

The PANcreatic Disease ReseArch (PANDoRA) consortium: Ten years’ experience of association studies to understand the genetic architecture of pancreatic cancer

Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies