Update of the risk assessment of brominated phenols and their derivatives in food.

The European Commission asked EFSA to update its 2012 risk assessment on brominated phenols and their derivatives in food, focusing on five bromophenols and one derivative: 2,4,6-tribromophenol (2,4,6-TBP), 2,4-dibromophenol (2,4-DBP), 4-bromophenol (4-BP), 2,6-dibromophenol (2,6-DBP), tetrabrominated bisphenol S (TBBPS), tetrabromobisphenol S bismethyl ether (TBBPS-BME). Based on the overall evidence, the CONTAM Panel considered in vivo genotoxicity of 2,4,6-TBP to be unlikely. Effects in liver and kidney were considered as the critical effects of 2,4,6-tribromophenol (2,4,6-TBP) in studies in rats. A BMDL10 of 353 mg/kg body weight (bw) per day for kidney papillary necrosis in male rats was identified and was selected as the reference point for the risk characterisation. The derivation of a health-based guidance value was not considered appropriate due to major limitations in the toxicological database. Instead, the margin of exposure (MOE) approach was applied to assess possible health concerns. Around 78,200 analytical results for 2,4,6-TBP in food were used to estimate dietary exposure for the European population. Considering the resulting MOE values, all far above an MOE of 6000 that does not raise a health concern, and accounting for the uncertainties affecting the exposure and hazard assessments, the CONTAM Panel concluded with at least 95% probability that the current dietary exposure to 2,4,6-TBP does not raise a health concern. Due to lack of occurrence data, no risk assessment could be performed for breastfed or formula-fed infants. No risk characterisation could be performed for any of the other brominated phenols and derivatives included in the assessment, due to lack of data both on the toxicity and occurrence.

BAG2, MAD2L1, and MDK are cancer-driver genes and candidate targets for novel therapies in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and the identification of novel druggable targets is urgently needed. In previous work, we identified 15 deregulated genes highly expressed in MPM tissues and correlated with a poor prognosis. Here, we validated these findings on an independent dataset of 211 MPM patients (EGA, EGAD00001001915) and on a panel of MPM cell lines. Furthermore, we carried out in vitro gene silencing followed by proliferation, cytotoxicity, caspase, and migration assays to define whether these targets could be cancer-driver genes. We ended up with three novel candidates (i.e., BAG2, MAD2L1, and MDK), whose encoded proteins could be exploited as druggable targets. Moreover, of novelty, immunohistochemistry analysis on tissues revealed that the overexpression of BAG2 and MAD2L1 could differentiate MPM from RMP patients. Furthermore, when we tested Neratinib (an inhibitor of MAD2L1) and iMDK (an inhibitor of MDK) we found that they are effective on MPM cells, in part phenocopying the effects of MAD2L1 and MDK gene silencing. In summary, in the present work, we report that BAG2, MAD2L1, and MDK are bona fide cancer-driver genes for MPM worth of further studies.

Comparative analysis of genetic variants in pleural fluids and solid tissue biopsies of pleural mesothelioma patients: Implications for molecular heterogeneity assessment.

Objectives: This study aims to determine whether the sequencing of DNA extracted from pleural fluids (PFs) of Pleural Mesothelioma (PM) patients accurately represents the genetic information obtained from the solid tissue counterpart biopsies with particular attention to the identification of single nucleotide variants (SNVs). Materials and methods: Single pleural biopsy, PFs, and blood were collected from PM patients. DNA was extracted from these samples and then subjected to Whole-Exome Sequencing. Results: A higher number of SNVs was identified in PFs than in solid tissue biopsies (STBs). Most SNVs were detected in PFs samples but not in STBs samples, while only a few SNVs were detected in STBs samples but not in PFs samples. Conclusion: The current findings support the notion that PFs might offer a more robust depiction of cancer's molecular diversity. Nonetheless, the current outcomes challenge the assertion that liquid biopsies can encompass the entirety of intra-patient variations. Indeed, a subset of potential cancer-driver SNVs was exclusively identified in STBs. However, relying solely on STBs would have precluded the detection of significant SNVs that were exclusively present in PFs. This implies that while PFs serve as a valuable complement to STBs, they do not supplant them.

Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model. METHODS: In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves. RESULTS: After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca2+ homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076). CONCLUSIONS: Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.

Polymorphism Pro64His within galectin-3 has functional consequences at proteome level in thyroid cells.

Introduction: The single nucleotide polymorphism (SNP) rs4644 at codon 64 of galectin-3 (gal-3, gene name: LGALS3), specifying the variant proline (P64) to histidine (H64), is known to affect the protein's functions and has been associated with the risk of several types of cancer, including differentiated thyroid carcinoma (DTC). Materials and methods: To deepen our understanding of the biological effects of this SNP, we analyzed the proteome of two isogenic cell lines (NC-P64 vs. NA-H64) derived from the immortalized non-malignant thyrocyte cell line Nthy-Ori, generated through the CRISPR-Cas9 technique to differ by rs4644 genotype. We compared the proteome of these cells to detect differentially expressed proteins and studied their proteome in relation to their transcriptome. Results: Firstly, we found, consistently with previous studies, that gal-3-H64 could be detected as a monomer, homodimer, and heterodimer composed of one cleaved and one uncleaved monomer, whereas gal-3-P64 could be found only as a monomer or uncleaved homodimer. Moreover, results indicate that rs4644 influences the expression of several proteins, predominantly upregulated in NA-H64 cells. Overall, the differential protein expression could be attributed to the altered mRNA expression, suggesting that rs4644 shapes the function of gal-3 as a transcriptional co-regulator. However, this SNP also appeared to affect post-transcriptional regulatory mechanisms for proteins whose expression was oppositely regulated compared to mRNA expression. It is conceivable that the rs4644-dependent activities of gal-3 could be ascribed to the different modalities of self-dimerization. Conclusion: Our study provided further evidence that rs4644 could affect the gal-3 functions through several routes, which could be at the base of differential susceptibility to diseases, as reported in case-control association studies.

Can single-use versus standard duodenoscope improve ergonomics in ERCP? A comparative, simulation-based pilot study.

Background and study aims Musculoskeletal disorders (MSDs) and injuries (MSIs) are frequent in gastrointestinal endoscopy. The aim of this study was to assess potential ergonomic advantages of a lighter single-use duodenoscope compared with a standard reusable one for endoscopists performing endoscopic retrograde cholangiopancreatography (ERCP). Methods Three experienced endoscopists performed an ergonomic, preclinical, comparative protocol-guided simulation study of a single-use and a standard reusable duodenoscope using an anatomic bench model. Surface EMG signals from left forearm and arm muscles were recorded. A commercial inertial sensor-based motion capture system was applied to record body posture as well. Results A significant lowering of root mean square amplitude and amplitude distribution of biceps brachii signal (ranging from 13% to 42%) was recorded in all the participants when using a single-use duodenoscope compared with a reusable one. An overall reduction of muscle activation amplitude and duration was also associated with the single-use duodenoscope for forearm muscles, with different behaviors among subjects. Participants spent most of the time in wrist extension (> 80%) and ulnar deviation (> 65%). A consistent pattern of functional range of motion employed for completing all procedures was observed. Conclusions Our study showed that a lighter scope has a promising effect in reducing upper arm muscle activity during ERCP with potential benefit on musculoskeletal health in the ERCP setting.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Disentangling organizational levers and economic benefits in transitional care programs: a systematic review and configurational analysis.

BACKGROUND: Promoting safe and efficient transitions of care is critical to reducing readmission rates and associated costs and improving the quality of patient care. A growing body of literature suggests that transitional care (TC) programs are effective in improving quality of life and reducing unplanned readmissions for several patient groups. TC programs are highly complex and multidimensional, requiring evidence on how specific practices and system characteristics influence their effectiveness in patient care, readmission reduction and costs. METHODS: Using a systematic review and a configurational approach, the study examines the role played by system characteristics (size, ownership, professional skills, technology used), the organizational components implemented, analyzing their combinations, and the potential economic impact of TC programs. RESULTS: The more organizational components are implemented, the greater the likelihood that a TC program will be successful in reducing readmission rates. Not all components have the same effect. The results show that certain components, 'post-discharge symptom monitoring and management' and 'discharge planning', are necessary but not sufficient to achieve the outcome. The results indicate the existence of two different combinations of components that can be considered sufficient for the reduction of readmissions. Furthermore, while system characteristics are underexplored, the study shows different ways of incorporating the skill mix of professionals and their mode of coordination in TC programs. Four organizational models emerge: the health-based monocentric, the social-based monocentric, the multidisciplinary team and the mono-specialist team. The economic impact of the programs is generally positive. Despite an increase in patient management costs, there is an overall reduction in all post-intervention costs, particularly those related to readmissions. CONCLUSIONS: The results underline the importance of examining in depth the role of system characteristics and organizational factors in facilitating the creation of a successful TC program. The work gives preliminary insights into how to systematize organizational practices and different coordination modes for facilitating decision-makers' choices in TC implementation. While there is evidence that TC programs also have economic benefits, the quality of economic evaluations is relatively low and needs further study.

Strategies for single base gene editing in an immortalized human cell line by CRISPR/Cas9 technology.

The use of CRISPR/Cas9 system has rapidly grown in the last years. Here, the optimization of gene editing of a single-nucleotide polymorphism in a human non-malignant somatic cell line of thyrocytes (Nthy-Ori) was described highlighting strategies for overcoming the problems concerning the delivery and off-targets. We employed both lentivirus and chemical lipids as delivery agents and two strategies for creating the double-strand breaks (DSB). The former induced a DSB by a classical Cas9 nuclease (standard strategy), while the second one employed a modified Cas9 creating a single-strand break (SSB). The knock-in was carried out using a single-stranded donor oligonucleotide or the HR410-PA donor vector (HR). The desired cells could be obtained by combining the double nickase system with the HR vector transfected chemically. This result could be due to the type of DSB, likely processed mainly by non-homologous end joining when blunt (standard strategy) and by HR when overhanging (double nickase). Our results showed that the double nickase is suitable for knocking-in the immortalized Nthy-Ori cell line, while the standard CRISPR/Cas9 system is suitable for gene knock-out creating in/del mutations. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03878-4.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

[Identifying population needs: methods of analysis and stratification]. / Identificare i bisogni della popolazione: metodi di analisi e di stratificazione.

. Identifying population needs: methods of analysis and stratification. In this article, examples of population stratification models used at the national level to identify different levels of needs and interventions are reported. Most models are based primarily on health data, diseases, clinical complexity, use of health services, hospitalizations, emergency room access, pharmaceutical prescriptions, and exemption codes. The limitations of these models relate to the availability and integration of data, as well as generalizability in different contexts. Moreover, to address the difficulty of implementing effective local interventions, the co-production or integration of social and health services is strongly suggested. Some survey techniques are presented to detect the needs, expectations, and resources of specific communities or populations.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression?

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evaluated whether 41 GWAS-identified risk variants for CLL could influence overall survival (OS) and disease progression, defined as time to first treatment (TTFT) in a cohort of 1039 CLL cases ascertained through the CRuCIAL consortium. Although this is the largest study assessing the effect of GWAS-identified susceptibility variants for CLL on OS, we only found a weak association of ten single nucleotide polymorphisms (SNPs) with OS (p < 0.05) that did not remain significant after correction for multiple testing. In line with these results, polygenic risk scores (PRSs) built with these SNPs in the CRuCIAL cohort showed a modest association with OS and a low capacity to predict patient survival, with an area under the receiver operating characteristic curve (AUROC) of 0.57. Similarly, seven SNPs were associated with TTFT (p < 0.05); however, these did not reach the multiple testing significance threshold, and the meta-analysis with previous published data did not confirm any of the associations. As expected, PRSs built with these SNPs showed reduced accuracy in prediction of disease progression (AUROC = 0.62). These results suggest that susceptibility variants for CLL do not impact overall survival and disease progression in CLL patients.

Genetic and non-genetic risk factors for early-onset pancreatic cancer.

BACKGROUND: Early-onset pancreatic cancer (EOPC) represents 5-10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. METHODS: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. RESULTS: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69-5.04, P = 1.44 × 10-4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41-65.50, P = 3.58 × 10-4). CONCLUSION: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.

Improvement of Symptoms in Patients Affected by Chronic Atrophic Gastritis Using L-Cysteine (Acetium®).

BACKGROUND: Chronic atrophic gastritis (CAG) alone is a precancerous condition for gastric cancer. Achlorhydria plays an important role in the formation of a class I carcinogen, acetaldehyde. L-cysteine has been claimed to bind acetaldehyde covalently. Symptoms are present in 55% of CAG patients, of whom 70% have upper gastrointestinal complaints. The aim of this study was to investigate the properties of L-cysteine in the modification of symptom patterns in CAG patients. METHODS: Consecutive patients with histological diagnosis of CAG (OLGA ≥1 with gastric corpus involvement) were evaluated with serological determination of gastric function, clinical assessment of symptoms using the visual analog score (VAS) and the global symptomatic score (GSS), and considered for therapy with L-cysteine, 300 mg daily. Data regarding symptoms were collected at enrollment and after 3, 6, 12, 18, and 24 months, with an ultimate follow-up of 2 years. RESULTS: A total of 330 patients with CAG were divided in group 1 (77 patients treated with L-cysteine) and group 2 (50 patients who received no specific treatment - control group). A statistically significant improvement in the VAS score (7.8 at baseline vs. 4.5 after 24 months; p < 0.01) was observed in patients treated with L-cysteine, while no significant changes in symptom pattern/intensity were recorded in the 2-year follow-up of untreated patients with CAG. CONCLUSIONS: Long-term treatment with L-cysteine provides symptom improvement in CAG patients and might be proposed as maintenance therapy in such patients.

Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk.

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.

Genetic signature of differentiated thyroid carcinoma susceptibility: a machine learning approach.

To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics and a machine learning (ML) classifier to describe cases and controls in three different datasets. Dataset 1 (649 DTC, 431 controls) has been previously genotyped in a genome-wide association study (GWAS) on Italian DTC. Dataset 2 (234 DTC, 101 controls) and dataset 3 (404 DTC, 392 controls) were genotyped. Associations of 171 SNPs reported to predispose to DTC in candidate studies were extracted from the GWAS of dataset 1, followed by replication of SNPs associated with DTC risk (P < 0.05) in dataset 2. The reliability of the identified SNPs was confirmed by PRS and Bayesian statistics after merging the three datasets. SNPs were used to describe the case/control state of individuals by ML classifier. Starting from 171 SNPs associated with DTC, 15 were positive in both datasets 1 and 2. Using these markers, PRS revealed that individuals in the fifth quintile had a seven-fold increased risk of DTC than those in the first. Bayesian inference confirmed that the selected 15 SNPs differentiate cases from controls. Results were corroborated by ML, finding a maximum AUC of about 0.7. A restricted selection of only 15 DTC-associated SNPs is able to describe the inner genetic structure of Italian individuals, and ML allows a fair prediction of case or control status based solely on the individual genetic background.