Blood Cadmium Level Is a Marker of Cancer Risk in Men.

Cadmium (Cd) is a known carcinogen, but its impact on cancer risk at lower concentrations is poorly understood. Previous studies on Cd and cancer risk in men show inconsistent results, prompting further investigation. A prospective cohort study involving 2956 men was conducted. Blood Cd levels were measured, and participants were followed for 78 months to assess cancer incidence. Men with high blood Cd levels (>0.71 µg/L) had a significantly increased risk of cancer compared to those with low levels (<0.19 µg/L) (HR 3.42, p < 0.001), particularly among non-smokers (HR 3.74, p = 0.003), individuals aged < 60 years (HR 2.79, p = 0.017), and ≥60 (HR 4.63, p = 0.004). The influence of smoking on cancer risk based on Cd levels was not significant in this study. Blood Cd levels may influence cancer risk in men, emphasizing the importance of minimizing Cd exposure to reduce risk. Confirmation of these results in other populations is essential for effective preventive measures against Cd-related cancers.

Blood Lead Level as Marker of Increased Risk of Ovarian Cancer in BRCA1 Carriers.

BRCA1 mutations substantially elevate the risks of breast and ovarian cancer. Various modifiers, including environmental factors, can influence cancer risk. Lead, a known carcinogen, has been associated with various cancers, but its impact on BRCA1 carriers remains unexplored. A cohort of 989 BRCA1 mutation carriers underwent genetic testing at the Pomeranian Medical University, Poland. Blood lead levels were measured using inductively coupled plasma mass spectrometry. Each subject was assigned to a category based on their tertile of blood lead. Cox regression analysis was used to assess cancer risk associations. Elevated blood lead levels (>13.6 µg/L) were associated with an increased risk of ovarian cancer (univariable: HR = 3.33; 95% CI: 1.23-9.00; p = 0.02; multivariable: HR = 2.10; 95% CI: 0.73-6.01; p = 0.17). No significant correlation was found with breast cancer risk. High blood lead levels are associated with increased risk of ovarian cancer in BRCA1 carriers, suggesting priority for preventive salpingo-oophorectomy. Potential risk reduction strategies include detoxification. Validation in diverse populations and exploration of detoxification methods for lowering lead levels are required.

Zinc and Its Antioxidant Properties: The Potential Use of Blood Zinc Levels as a Marker of Cancer Risk in BRCA1 Mutation Carriers.

BRCA1 mutations predispose women to breast and ovarian cancer. The anticancer effect of zinc is typically linked to its antioxidant abilities and protecting cells against oxidative stress. Zinc regulates key processes in cancer development, including DNA repair, gene expression, and apoptosis. We took a blood sample from 989 female BRCA1 mutation carriers who were initially unaffected by cancer and followed them for a mean of 7.5 years thereafter. There were 172 incident cases of cancer, including 121 cases of breast cancer, 29 cases of ovarian cancers, and 22 cancers at other sites. A zinc level in the lowest tertile was associated with a modestly higher risk of ovarian cancer compared to women with zinc levels in the upper two tertiles (HR = 1.65; 95% CI 0.80 to 3.44; p = 0.18), but this was not significant. Among those women with zinc levels in the lowest tertile, the 10-year cumulative risk of ovarian cancer was 6.1%. Among those in the top two tertiles of zinc level, the ten-year cumulative risk of ovarian cancer was 4.7%. There was no significant association between zinc level and breast cancer risk. Our preliminary study does not support an association between serum zinc level and cancer risk in BRCA1 mutation carriers.

Selenium and Arsenic Levels, Prevalence of Common Variants of Genes Involved in Their Metabolism, and Psoriasis Disease.

Using an Inductively Coupled Plasma Mass Spectrometer we measured the concentration of selenium and arsenic in serum and blood samples from 336 unselected psoriatic patients and 336 matched healthy controls to evaluate any associations with the clinical course of the disease. We genotyped 336 patients and 903 matched controls to evaluate the prevalence of SOD2 (rs4880), CAT (rs1001179), GPX1 (rs1050450), and DMGDH (rs921943) polymorphisms using Taqman assays. The mean selenium (Se) level in serum was 74 µg/L in patients and 86 µg/L in controls (p < 0.001). The mean Se level in blood was 95 µg/L in patients and 111 µg/L in controls (p < 0.001). Psoriasis risk was greatest among participants with the lowest serum (<68.75 µg/L, OR: 8.30; p < 0.001) and lowest blood concentrations of Se (<88.04 µg/L, OR: 10.3; p < 0.001). Similar results were observed in subgroups of males and females. We found an inverse correlation of selenium levels with PASI, NAPSI, and BSA scores. There was no significant difference in the distribution of the CAT, GPX1, DMGDH, and SOD2 polymorphisms. Among carriers of rs4880, rs1001179, and rs921943 polymorphisms, blood selenium levels were significantly lower. The mean arsenic level in serum was 0.79 µg/L in patients and 0.7 µg/L in controls (p = 0.2). The mean concentration in blood was 1.1 µg/L in patients and 1.3 µg/L in controls (p < 0.001). In conclusion, we found that lower selenium levels, in blood and serum, are associated with psoriasis risk and its more severe course. Future prospective studies should focus on the optimalisation of the concentration of this trace element not only for prophylactic guidance but also to support the treatment of this disease.

Correlation between Selenium and Zinc Levels and Survival among Prostate Cancer Patients.

The most prevalent type of cancer among males is prostate cancer. Survival is considered quite good, but it can be further improved when risk factors are optimized. One of these factors is micronutrients, including Se and Zn. To our knowledge, the interaction between Se and Zn and prostate cancer remains undescribed. This study aimed to investigate the optimal levels of selenium (Se) and zinc (Zn) and their impact on the survival of individuals diagnosed with prostate cancer. A total of 338 prostate cancer patients were enrolled in this study, which was conducted in Poland between 2009 and 2015. Mass spectrometry, which uses inductively coupled plasma mass, was used to assess serum element levels before treatment. The study participants were categorized into quartiles (QI-QIV) based on the distributions of Se and Zn levels observed among surviving participants. Cox regression was used to assess the association between serum Se and Zn levels and the survival of prostate cancer patients. Our results reveal the effect of combined Se and Zn levels on survival in prostate cancer patients (SeQI-ZnQI vs. SeQIV-ZnQIV; HR = 20.9). These results need further research to establish Se/Zn norms for different populations.

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma.

Phyllodes tumours (PTs) are rare fibroepithelial lesions of the breast that are classified as benign, borderline, or malignant. As little is known about the molecular underpinnings of PTs, current diagnosis relies on histological examination. However, accurate classification is often difficult, particularly for distinguishing borderline from malignant PTs. Furthermore, PTs can be misdiagnosed as other tumour types with shared histological features, such as fibroadenoma and metaplastic breast cancers. As DNA methylation is a recognised hallmark of many cancers, we hypothesised that DNA methylation could provide novel biomarkers for diagnosis and tumour stratification in PTs, whilst also allowing insight into the molecular aetiology of this otherwise understudied tumour. We generated whole-genome methylation data using the Illumina EPIC microarray in a novel PT cohort (n = 33) and curated methylation microarray data from published datasets including PTs and other potentially histopathologically similar tumours (total n = 817 samples). Analyses revealed that PTs have a unique methylome compared to normal breast tissue and to potentially histopathologically similar tumours (metaplastic breast cancer, fibroadenoma and sarcomas), with PT-specific methylation changes enriched in gene sets involved in KRAS signalling and epithelial-mesenchymal transition. Next, we identified 53 differentially methylated regions (DMRs) (false discovery rate < 0.05) that specifically delineated malignant from non-malignant PTs. The top DMR in both discovery and validation cohorts was hypermethylation at the HSD17B8 CpG island promoter. Matched PT single-cell expression data showed that HSD17B8 had minimal expression in fibroblast (putative tumour) cells. Finally, we created a methylation classifier to distinguish PTs from metaplastic breast cancer samples, where we revealed a likely misdiagnosis for two TCGA metaplastic breast cancer samples. In conclusion, DNA methylation alterations are associated with PT histopathology and hold the potential to improve our understanding of PT molecular aetiology, diagnostics, and risk stratification. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Alteration of DNA Methylation and Epigenetic Scores Associated With Features of Schizophrenia and Common Variant Genetic Risk.

BACKGROUND: Unpacking molecular perturbations associated with features of schizophrenia is a critical step toward understanding phenotypic heterogeneity in this disorder. Recent epigenome-wide association studies have uncovered pervasive dysregulation of DNA methylation in schizophrenia; however, clinical features of the disorder that account for a large proportion of phenotypic variability are relatively underexplored. METHODS: We comprehensively analyzed patterns of DNA methylation in a cohort of 381 individuals with schizophrenia from the deeply phenotyped Australian Schizophrenia Research Bank. Epigenetic changes were investigated in association with cognitive status, age of onset, treatment resistance, Global Assessment of Functioning scores, and common variant polygenic risk scores for schizophrenia. We subsequently explored alterations within genes previously associated with psychiatric illness, phenome-wide epigenetic covariance, and epigenetic scores. RESULTS: Epigenome-wide association studies of the 5 primary traits identified 662 suggestively significant (p < 6.72 × 10-5) differentially methylated probes, with a further 432 revealed after controlling for schizophrenia polygenic risk on the remaining 4 traits. Interestingly, we uncovered many probes within genes associated with a variety of psychiatric conditions as well as significant epigenetic covariance with phenotypes and exposures including acute myocardial infarction, C-reactive protein, and lung cancer. Epigenetic scores for treatment-resistant schizophrenia strikingly exhibited association with clozapine administration, while epigenetic proxies of plasma protein expression, such as CCL17, MMP10, and PRG2, were associated with several features of schizophrenia. CONCLUSIONS: Our findings collectively provide novel evidence suggesting that several features of schizophrenia are associated with alteration of DNA methylation, which may contribute to interindividual phenotypic variation in affected individuals.

Using Genetics to Inform Interventions Related to Sodium and Potassium in Hypertension.

BACKGROUND: Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetics of BP could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels. METHODS: In this observational genetic study, we leveraged cross-sectional data from up to 296 475 genotyped individuals drawn from the UK Biobank cohort for whom BP and urinary electrolytes (sodium and potassium), biomarkers of sodium and potassium intake, were measured. Biologically directed genetic scores for BP were constructed specifically among pathways related to sodium and potassium biology (pharmagenic enrichment scores), as well as unannotated genome-wide scores (conventional polygenic scores). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on BP. RESULTS: Genetic risk and urinary electrolytes both independently correlated with BP. However, urinary sodium was associated with a larger BP increase among individuals with higher genetic risk in sodium- and potassium-related pathways than in those with comparatively lower genetic risk. For example, each SD in urinary sodium was associated with a 1.47-mm Hg increase in systolic BP for those in the top 10% of the distribution of genetic risk in sodium and potassium transport pathways versus a 0.97-mm Hg systolic BP increase in the lowest 10% (P=1.95×10-3). This interaction with urinary sodium remained when considering estimated glomerular filtration rate and indexing sodium to urinary creatinine. There was no strong evidence of an interaction between urinary sodium and a standard genome-wide polygenic score of BP. CONCLUSIONS: The data suggest that genetic risk in sodium and potassium pathways could be used in a precision medicine model to direct interventions more specifically in the management of hypertension. Intervention studies are warranted.

MTHFR C677T and A1298C polymorphism's effect on risk of colorectal cancer in Lynch syndrome.

Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10-80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals.

Self-reported traumatic brain injury in a sample of impulsive violent offenders: neuropsychiatric correlates and possible "dose effects".

Background: Traumatic brain injury (TBI) is a major public health problem that may be associated with numerous behavioral problems, including impulsivity, aggression and violence. Rates of self-reported TBI are high within offender populations, but the extent to which TBI is causally implicated in causing illegal behavior is unclear. This study examined the psychological and functional correlates of histories of traumatic brain injury in a sample of impulsive violent offenders. Methods: Study participants, all men, had been recruited to participate in a randomized controlled trial of sertraline to reduce recidivism. Study entry criteria were an age of at least 18 years, a documented history of two or more violent offenses and a score of 70 or above on the Barratt Impulsiveness Scale. An extensive list of standardized questionnaires was administered to obtain information on previous TBI and other neuropsychiatric conditions or symptoms. Results: In the sample of 693 men, 66% were aged between 18 and 35 years old, and 55% gave a history of TBI ("TBI+"). Overall, 55% of study participants reported at least one TBI. High levels of neuropsychiatric symptomatology were reported. In 75% of TBI+ individuals, their most severe TBI (by self-report) was associated with loss of consciousness (LOC) < 30 min. Compared to TBI- (those without history of TBI) participants, TBI+ individuals were more impulsive (Eysenck Impulsivity), irritable, angry, and reported higher levels of assaultive behavior, depressive symptomology, alcohol use disorder, suicidal ideation, suicide attempts, and lower quality of life. Potential "dose effects" of TBI severity and frequency in terms of neuropsychiatric symptomatology were identified. Conclusion: Like other studies of offender populations, single and multiple TBIs were very common. The associations of TBI, TBI severity, and TBI frequency (i.e., TBI "burden") with adverse neuropsychiatric phenomena suggest TBI contributes importantly to offender morbidity but the select nature of the sample and cross-sectional study design constrain the interpretation of these findings.

Evaluation of a Multi-Gene Methylation Blood-Test for the Detection of Colorectal Cancer.

Circulating tumour DNA biomarkers are an expanding field in oncology research that offer great potential but are currently often limited in value by overall cost. The aim of this study was to evaluate the efficacy of a novel multi-gene methylation blood test for the identification of colorectal cancer and throughout the spectrum of colorectal disease. Participants were recruited either prior to resection for known CRC or prior to screening colonoscopy after a positive faecal immunochemical test. Blood was collected from participants prior to their procedure being performed. The plasma was separated, and multiplex MethylLight droplet digital PCR was used to analyse for the presence of four methylated genes: SDC2, NPY, IKZF1 and SEPT9. A total of 537 participants underwent analysis. The SDC2/NPY genes showed a sensitivity of 33-54% and a specificity of 72-96%, whilst the IKZF1/SEPT9 genes showed a sensitivity of 19-42% and a specificity of 88-96%. Combining the two tests did not significantly increase the test accuracy. The sensitivity for advanced adenoma was 2-15%. There was a significant difference in the frequency of detectable methylation between the participants with CRC and those without CRC. However, neither the sensitivity nor the specificity was superior to current diagnostic screening tests.

DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes.

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82-0.89, p = 1.22 × 10-29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66-0.76, p = 9.07 × 10-17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

Evaluation of Cell-Specific Epigenetic Age Acceleration in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), accelerated aging of the immune system (immunosenescence) may be associated with disease onset or drive progression. DNA methylation (DNAm) is an epigenetic factor that varies among lymphocyte subtypes, and cell-specific DNAm is associated with MS. DNAm varies across the life span and can be used to accurately estimate biological age acceleration, which has been linked to a range of morbidities. The objective of this study was to test for cell-specific epigenetic age acceleration (EAA) in people with MS. METHODS: This was a case-control study of EAA using existing DNAm data from several independent previously published studies. Data were included if .idat files from Illumina 450K or EPIC arrays were available for both a case with MS and an age-matched and sex-matched control, from the same study. Multifactor statistical modeling was performed to assess the primary outcome of EAA. We explored the relationship of EAA and MS, including interaction terms to identify immune cell-specific effects. Cell-sorted DNA methylation data from 3 independent datasets were used to validate findings. RESULTS: We used whole blood DNA methylation data from 583 cases with MS and 643 non-MS controls to calculate EAA using the GrimAge algorithm. The MS group exhibited an increased EAA compared with controls (approximately 9 mths, 95% CI 3.6-14.4), p = 0.001). Statistical deconvolution showed that EAA is associated with MS in a B cell-dependent manner (ß int = 1.7, 95% CI 0.3-2.8), p = 0.002), irrespective of B-cell proportions. Validation analysis using 3 independent datasets enriched for B cells showed an EAA increase of 5.1 years in cases with MS compared with that in controls (95% CI 2.8-7.4, p = 5.5 × 10-5). By comparison, there was no EAA difference in MS in a T cell-enriched dataset. We found that EAA was attributed to the DNAm surrogates for Beta-2-microglobulin (difference = 47,546, 95% CI 10,067-85,026; p = 7.2 × 10-5), and smoking pack-years (difference = 8.1, 95% CI 1.9-14.2, p = 0.002). DISCUSSION: This study provides compelling evidence that B cells exhibit marked EAA in MS and supports the hypothesis that premature B-cell immune senescence plays a role in MS. Future MS studies should focus on age-related molecular mechanisms in B cells.

Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing.

BACKGROUND: Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones. METHODS: We performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants. RESULTS: We identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer. CONCLUSIONS: Identification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.

Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis.

Introduction: Multiple Sclerosis (MS) has a complex pathophysiology that involves genetic and environmental factors. DNA methylation (DNAm) is one epigenetic mechanism that can reversibly modulate gene expression. Cell specific DNAm changes have been associated with MS, and some MS therapies such as dimethyl fumarate can influence DNAm. Interferon Beta (IFNß), was one of the first disease modifying therapies in multiple sclerosis (MS). However, how IFNß reduces disease burden in MS is not fully understood and little is known about the precise effect of IFNß treatment on methylation. Methods: The objective of this study was to determine the changes in DNAm associated with INFß use, using methylation arrays and statistical deconvolutions on two separate datasets (total ntreated = 64, nuntreated = 285). Results: We show that IFNß treatment in people with MS modifies the methylation profile of interferon response genes in a strong, targeted, and reproducible manner. Using these identified methylation differences, we constructed a methylation treatment score (MTS) that is an accurate discriminator between untreated and treated patients (Area under the curve = 0.83). This MTS is time-sensitive and in consistent with previously identified IFNß treatment therapeutic lag. This suggests that methylation changes are required for treatment efficacy. Overrepresentation analysis found that IFNß treatment recruits the endogenous anti-viral molecular machinery. Finally, statistical deconvolution revealed that dendritic cells and regulatory CD4+ T cells were most affected by IFNß induced methylation changes. Discussion: In conclusion, our study shows that IFNß treatment is a potent and targeted epigenetic modifier in multiple sclerosis.

Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels.

To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.

The utilisation of digital droplet PCR to enhance the diagnosis of bladder and pancreaticobiliary tumours in cytology specimens.

BACKGROUND: Digital droplet PCR (ddPCR) is a relatively new technique used to detect molecular alterations with unprecedented precision and accuracy. It is particularly useful for detecting point mutations and copy number variation (CNV) in samples with small amounts of target DNA. This proof of principle study was conducted to see if ddPCR technology could be applied to cytology specimens to detect molecular alterations which may influence diagnostic decision making. METHODS: A range of cytological specimens derived from bladder or pancreaticobiliary origin, with varying diagnoses but with an emphasis on abnormality, underwent ddPCR testing. DNA was manually extracted from Thinprep vials, cell blocks or direct fine needle aspiration smears. ddPCR was performed using two somatic point mutations TP53 R248W and TP53 R273H assays for both urine and pancreaticobiliary cytology specimens. Three CNV assays; CDKN2A, E2F3 and YWHAZ were applied to urine samples. SMAD4 and CDKN2A CNVs were applied to the pancreaticobiliary samples. RESULTS: 16 of 21 urine specimens showed molecular alterations using ddPCR testing. 12 of those 16 cases were associated with malignant outcomes. The pancreaticobiliary specimens showed 14 of 37 specimens with molecular alterations, all of which were associated with carcinoma. We demonstrated an increasing percentage of molecular aberrations associated with increasing severity of cytological results. CONCLUSION: Our results have shown that ddPCR can identify both mutations and CNVs in urine and pancreaticobiliary cytology derived samples. Being able to detect these molecular alterations may reduce the number of equivocal results leading to more timely and informed patient management decisions.

Prevalence and clinical significance of co-existing mutations in MED12 and FH in uterine fibroids of Australian women.

Uterine fibroids are exceedingly common benign tumours of the female reproductive system and cause severe symptoms, including acute pain, bleeding, and infertility. Fibroids are frequently associated with genetic alterations affecting mediator complex subunit 12 (MED12), fumarate hydratase (FH), high mobility group AT-hook 2 (HMGA2) and collagen, type IV alpha 5 and alpha 6 (COL4A5-COL4A6). Recently, we reported MED12 exon 2 mutations in 39 out of 65 uterine fibroids (60%) from 14 Australian patients. The aim of this study was to evaluate the status of FH mutations in MED12 mutation-positive and mutation-negative uterine fibroids. FH mutation screening of altogether 65 uterine fibroids and corresponding adjacent normal myometrium (n = 14) was carried out by Sanger sequencing. Three out of 14 patients displayed somatic mutations in FH exon 1 in addition to harbouring MED12 mutation in uterine fibroids. This study is the first to report that the mutations in MED12 and FH co-exist in uterine fibroids of Australian women.