Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk.

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.

Physical Activity, Sedentary Behavior, and Pancreatic Cancer Risk: A Mendelian Randomization Study.

Pancreatic cancer is currently the seventh leading cause of cancer death worldwide. Understanding whether modifiable factors increase or decrease the risk of this disease is central to facilitating primary prevention. Several epidemiological studies have described the benefits of physical activity, and the risks associated with sedentary behavior, in relation to cancer. This study aimed to assess evidence of causal effects of physical activity and sedentary behavior on pancreatic cancer risk. We conducted a two-sample Mendelian randomization study using publicly available data for genetic variants associated with physical activity and sedentary behavior traits and genetic data from the Pancreatic Cancer Cohort Consortium (PanScan), the Pancreatic Cancer Case-Control Consortium (PanC4), and the FinnGen study for a total of 10 018 pancreatic cancer cases and 266 638 controls. We also investigated the role of body mass index (BMI) as a possible mediator between physical activity and sedentary traits and risk of developing pancreatic cancer. We found evidence of a causal association between genetically determined hours spent watching television (hours per day) and increased risk of pancreatic cancer for each hour increment (PanScan-PanC4 odds ratio = 1.52, 95% confidence interval 1.17-1.98, P = .002). Additionally, mediation analysis showed that genetically determined television-watching time was strongly associated with BMI, and the estimated proportion of the effect of television-watching time on pancreatic cancer risk mediated by BMI was 54%. This study reports the first Mendelian randomization-based evidence of a causal association between a measure of sedentary behavior (television-watching time) and risk of pancreatic cancer and that this is strongly mediated by BMI. Summary: Pancreatic cancer is a deadly disease that is predicted to become the second leading cause of cancer-related deaths by 2030. Physical activity and sedentary behaviors have been linked to cancer risk and survival. However, there is limited research on their correlation with pancreatic cancer. To investigate this, we used a Mendelian randomization approach to examine the genetic predisposition to physical activity and sedentariness and their relation to pancreatic cancer risk, while excluding external confounders. Our findings revealed a causal link between the time spent watching television and an increased risk of pancreatic cancer. Additionally, we determined that over half of the effect of watching television on pancreatic risk is mediated by the individual's BMI.

The local environment and germline genetic variation predict cancer risk in the UK Biobank prospective cohort.

BACKGROUND: There is a growing body of evidence on the effect of the local environment exposure on cancer susceptibility. Nonetheless, several of the associations remain controversial. Moreover, our understanding of the possible interaction between the local environment and the genetic variability is still very limited. OBJECTIVE: The aim of this study was to clarify the role of the local environment and its possible interplay with genetics on common cancers development. METHODS: Using the UK Biobank (UKBB) prospective cohort, we selected 12 local environment exposures: nitrogen oxides, nitrogen dioxides, particulate matter (10 and 2.5 µm), noise pollution, urban traffic, living distance from the coast, percentage of greenspace, natural environment, water, and domestic garden within 1000 m from the residential coordinates of each participant. All these exposures were tested for association with 17 different types of cancer for a total of 53,270 cases and 302,645 controls. Additionally, a polygenic score (PGS) was computed for each cancer, to test possible gene-environment interactions. Finally, mediation analyses were carried out. RESULTS: Thirty-six statistically significant associations considering multiple testing (p < 2.19 × 10-4) were observed. Among the novel associations we observed that individuals living farther from the coast had a higher risk of developing prostate cancer (OR = 1.13, CI95% = 1.06-1.20, P = 1.98 × 10-4). This association was partially mediated by physical activity (indirect effect (IE) = -8.48 × 10-7) and the time spent outdoor (IE = 9.07 × 10-6). All PGSs showed statistically significant associations. Finally, genome-environment interaction analysis showed that local environment and genetic variability affect cancer risk independently. DISCUSSION: Living close to the coast and air pollution were associated with a decreased risk of prostate cancer and skin melanoma, respectively. These findings from the UKBB support the role of the local environment on cancer development, which is independent from genetics and may be mediated by several lifestyle factors.

Analysis of exposome and genetic variability suggests stress as a major contributor for development of pancreatic ductal adenocarcinoma.

BACKGROUND: The current knowledge on pancreatic ductal adenocarcinoma (PDAC) risk factors is limited and no study has comprehensively tested the exposome in combination with the genetic variability in relation to the disease susceptibility. AIM: The aim of this study was to analyze the exposome and its interaction with known genetic susceptibility loci, in relation to PDAC risk. METHODS: A case-control study nested in UK Biobank cohort was conducted on 816 PDAC cases and 302,645 controls. A total of 347 exposure variables, and a polygenic risk score (PRS) were analyzed through logistic regression. Gene-environment interaction analyses were conducted. RESULTS: A total of 52 associations under the Bonferroni corrected threshold of p < 1.46 × 10-4 were observed. Known risk factors such as smoking, pancreatitis, diabetes, PRS, heavy alcohol drinking and overweight were replicated in this study. As for novel associations, a clear indication for length and intensity of mobile phone use and the stress-related factors and stressful events with increase of PDAC risk was observed. Although the PRS was associated with PDAC risk (P = 2.09 × 10-9), statistically significant gene-exposome interactions were not identified. CONCLUSION: In conclusion, our results suggest that a stressful lifestyle and sedentary behaviors may play a major role in PDAC susceptibility independently from the genetic background.

Long or short? Telomere length and pancreatic cancer and its precursor lesions, a narrative review.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, with a survival approaching only 11% at five years after diagnosis. In the last 15 years, telomere length measured in leukocyte (LTL) has been studied in relation to PDAC risk. The majority of the studies reported an association between short LTL and increased PDAC risk, but the results are heterogeneous. Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) gene as susceptibility loci for PDAC. Polygenic risk scores (PRS) computed using SNPs associated with LTL have been tested in relation to PDAC susceptibility with various methods and giving contrasting results. The aim of this review is to analyze all publications carried out specifically on LTL, considering LTL measured with qPCR and with genetic proxies, and PDAC risk. Additionally, we will give an overview of the most relevant associations between SNPs in telomere associated genes and PDAC, to answer the question shorter or longer? Which one of the two is associated with 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.

Maternal anthropometric variables and clinical factors shape neonatal microbiome.

Recent studies indicate the existence of a complex microbiome in the meconium of newborns that plays a key role in regulating many host health-related conditions. However, a high variability between studies has been observed so far. In the present study, the meconium microbiome composition and the predicted microbial metabolic pathways were analysed in a consecutive cohort of 96 full-term newborns. The effect of maternal epidemiological variables on meconium diversity was analysed using regression analysis and PERMANOVA. Meconium microbiome composition mainly included Proteobacteria (30.95%), Bacteroidetes (23.17%) and Firmicutes (17.13%), while for predicted metabolic pathways, the most abundant genes belonged to the class "metabolism". We observed a significant effect of maternal Rh factor on Shannon and Inverse Simpson indexes (p = 0.045 and p = 0.049 respectively) and a significant effect of delivery mode and maternal antibiotic exposure on Jaccard and Bray-Curtis dissimilarities (p = 0.001 and 0.002 respectively), while gestational age was associated with observed richness and Shannon indexes (p = 0.018 and 0.037 respectively), and Jaccard and Bray-Curtis dissimilarities (p = 0.014 and 0.013 respectively). The association involving maternal Rh phenotype suggests a role for host genetics in shaping meconium microbiome prior to the exposition to the most well-known environmental variables, which will influence microbiome maturation in the newborn.

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 < 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 × 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. IMPACT: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

Genetic polymorphisms in inflammatory genes and pancreatic cancer risk: a two-phase study on more than 14 000 individuals.

There is overwhelming evidence that inflammation plays a key role in the pathogenesis of cancer and its progression. Inflammation is regulated through a complex network of genes and polymorphic variants in these genes have been found to be associated to risk of various human cancers, alone or in combination with environmental variables. Despite this, not much is known on the genetic variability of genes that regulate inflammation and risk of pancreatic ductal adenocarcinoma (PDAC). We performed a two-phase association study considering the genetic variability of 76 genes that are key players in inflammatory response. We analysed tagging single nucleotide polymorphisms (SNPs) and regulatory SNPs on 7207 PDAC cases and 7063 controls and observed several associations with PDAC risk. The most significant association was between the carriers of the A allele of the CCL4-rs1719217 polymorphism, which was reported to be also associated with the expression level of the CCL4 gene, and increased risk of developing PDAC (odds ratio = 1.12, 95% confidence interval = 1.06-1.18, P = 3.34 × 10-5). This association was significant also after correction for multiple testing, highlighting the importance of using potentially functional SNPs in order to discover more genetic variants associated with PDAC risk.