Mapping breast and prostate cancer in the Brazilian public health system: study protocol of the Onco-Genomas Brasil.

Background: Breast and prostate cancers are the most common malignancies diagnosed in women and men respectively, and present with great clinical heterogeneity, even in tumors with the same histology and same site of origin. Somatic and germline molecular alterations in DNA may have prognostic and predictive impact, influencing response to therapies and overall survival. Our aim is to characterize the somatic and germline genomic landscape of women with locally advanced HER2-positive breast cancer and men with metastatic prostate cancer in Brazil. Secondarily, we aim to identify genetic variants associated with tumor prognosis and treatment response, identify patients carrying pathogenic alterations in cancer-predisposing genes, and characterize the genetic ancestry of the population included in the study. Methods: This observational multicenter cohort study will include 550 adult patients from the five macro-regions of Brazil, divided into two arms: 1) breast cancer and 2) prostate cancer. Clinical and pathological data will be collected, as well as DNA samples from peripheral blood and tumor samples. In arm 1, the inclusion criteria are a histological diagnosis of breast carcinoma with overexpression of HER-2, clinical stage II or III, and current neoadjuvant treatment with chemotherapy plus trastuzumab. In arm 2, the criterion is a histological diagnosis of prostate adenocarcinoma, clinical stage IV. Whole-exome sequencing (WES) will be performed to identify variants that may be drivers and/or actionable in a specific patient or tumor. These variants will be interpreted and classified according to their population frequencies, in silico predictors, functional studies, and literature data, following international guidelines proposed by expert societies. Discussion: This trial will contribute to the construction of a robust database that should provide a better understanding of the genomic profile of patients with breast and prostate cancer in Brazil. Considering the miscegenation of the Brazilian population, knowledge generated from these data will have implications for future studies of this specific population. Clinical trial registration: [clinicaltrial.gov], identifier [NCT05306600].

Intimate Partner Violence and Women's Mental Health during the COVID-19 Pandemic in Brazil.

BACKGROUND: Intimate partner violence (IPV) increased extensively around the world during the pandemic, causing severe women's mental health damages. However, there are no studies showing these effects in Brazil. PURPOSE: To assess the perpetration of IPV and the presence of depression and suicidal ideation in women living in Brazil during the pandemic. METHODS: Cross-sectional online survey including women living in Brazil from July 2020 to Jun 2021. Participants answered a 43-item self-applied questionnaire exploring their characteristics and life changes due to the pandemic (CoRonavIruS Health Impact Survey), IPV (World Health Organization Violence Against Women) and depressive symptoms or suicidal ideation (Patient Health Questionnaire-9). We used multiple Poisson regression analyses with robust variance to model associations between IPV and mental health outcomes, considering as covariates aspects of social vulnerability. RESULTS: We found a high frequency of IPV (33.3%), depression (36.1%) and suicidal ideation (19.8%) among the participants. IPV was significantly associated with depression (PR=1.502, p=0.001 for one type of IPV; PR=2.702, p<0.001 for two or three types of IPV) and suicidal ideation (PR=2.264, p<0.001 for one type of VPI; PR=3.272, p<0.001 for two or three types of IPV). Food insecurity, being black, lower educational levels and being in a relationship with a person of the same gender were associated with one or both mental health outcomes. CONCLUSIONS: We demonstrated an association of IPV with higher frequencies of depression and suicidal ideation in women living in Brazil during the COVID-19 pandemic, highlighting the urgency of strengthening strategies to protect women during adversities.

Telomere length and epigenetic age acceleration in adolescents with anxiety disorders.

Evidence on the relationship between genetics and mental health are flourishing. However, few studies are evaluating early biomarkers that might link genes, environment, and psychopathology. We aimed to study telomere length (TL) and epigenetic age acceleration (AA) in a cohort of adolescents with and without anxiety disorders (N = 234). We evaluated a representative subsample of participants at baseline and after 5 years (n = 76) and categorized them according to their anxiety disorder diagnosis at both time points: (1) control group (no anxiety disorder, n = 18), (2) variable group (anxiety disorder in one evaluation, n = 38), and (3) persistent group (anxiety disorder at both time points, n = 20). We assessed relative mean TL by real-time quantitative PCR and DNA methylation by Infinium HumanMethylation450 BeadChip. We calculated AA using the Horvath age estimation algorithm and analyzed differences among groups using generalized linear mixed models. The persistent group of anxiety disorder did not change TL over time (p = 0.495). The variable group had higher baseline TL (p = 0.003) but no accelerated TL erosion in comparison to the non-anxiety control group (p = 0.053). Furthermore, there were no differences in AA among groups over time. Our findings suggest that adolescents with chronic anxiety did not change telomere length over time, which could be related to a delay in neuronal development in this period of life.

Anxiety disorders in childhood are associated with youth IL-6 levels: A mediation study including metabolic stress and childhood traumatic events.

Anxiety disorders (ADs) are chronic conditions that often have their onset in childhood and adolescence. Inflammation and oxidative stress markers have been associated with the vulnerability to ADs, however it is not known if ADs in childhood can influence these biomarkers levels longitudinally. This study aims to investigate a possible association between ADs and serum levels of IL-10, IL-6, IL-1ß, TNF-α, BDNF, and protein carbonyl content, assessed after 5 years of follow-up. Moreover, we studied possible mediators for these associations, including physical activity, metabolic markers and childhood trauma. From 240 individuals evaluated at baseline, 73 were re-evaluated in the follow-up. Psychiatric diagnoses were assessed with the K-SADS or the MINI and child trauma questionnaire (CTQ) to evaluate presence of trauma. We searched serum levels of IL-10, IL-6, IL-1ß and TNF-α (flow cytometry), BDNF (sandwich-ELISA) and carbonyl content in proteins (PCC method). We found a significant direct association between ADs at baseline and log IL-6 (B = 0.34, S.E. = 0.11, p = 0.002) and between AD and log BDNF (B = -0.10, S.E. = 0.05, p = 0.033) five years later. Searching for possible mediators of these association, we found that levels of HDL-cholesterol (ΔB = -0.148) partially mediated the association between ADs and IL-6. No significant mediators were found in the association between ADs and BDNF. Moreover, this association is no longer significant after controlling for the presence of depression. Our results demonstrated that previous AD diagnosis was associated with higher levels of IL-6 in the follow-up evaluation, suggesting that the presence of anxiety in childhood could influence altered inflammatory markers.

Sex differences in DNA methylation of the cord blood are related to sex-bias psychiatric diseases.

Sex differences in the prevalence of psychiatric disorders are well documented, with exposure to stress during gestation differentially impacting females and males. We explored sex-specific DNA methylation in the cord blood of 39 females and 32 males born at term and with appropriate weight at birth regarding their potential connection to psychiatric outcomes. Mothers were interviewed to gather information about environmental factors (gestational exposure) that could interfere with the methylation profiles in the newborns. Bisulphite converted DNA was hybridized to Illumina HumanMethylation450 BeadChips. Excluding XYS probes, there were 2,332 differentially methylated CpG sites (DMSs) between sexes, which were enriched within brain modules of co-methylated CpGs during brain development and also differentially methylated in the brains of boys and girls. Genes associated with the DMSs were enriched for neurodevelopmental disorders, particularly for CpG sites found differentially methylated in brain tissue between patients with schizophrenia and controls. Moreover, the DMS had an overlap of 890 (38%) CpG sites with a cohort submitted to toxic exposition during gestation. This study supports the evidences that sex differences in DNA methylation of autosomes act as a primary driver of sex differences that are found in psychiatric outcomes.

Innate immune response is differentially dysregulated between bipolar disease and schizophrenia.

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric conditions with a neurodevelopmental component. Genetic findings indicate the existence of an overlap in genetic susceptibility across the disorders. Also, image studies provide evidence for a shared neurobiological basis, contributing to a dimensional diagnostic approach. This study aimed to identify the molecular mechanisms that differentiate SZ and BD patients from health controls but also that distinguish both from health individuals. Comparison of gene expression profiling in post-mortem brains of both disorders and health controls (30 cases), followed by a further comparison between 29 BD and 29 SZ revealed 28 differentially expressed genes. These genes were used in co-expression analysesthat revealed the pairs CCR1/SERPINA1, CCR5/HCST, C1QA/CD68, CCR5/S100A11 and SERPINA1/TLR1 as presenting the most significant difference in co-expression between SZ and BD. Next, a protein-protein interaction (PPI) network using the 28 differentially expressed genes as seeds revealed CASP4, TYROBP, CCR1, SERPINA1, CCR5 and C1QA as having a central role in the diseases manifestation. Both co-expression and network topological analyses pointed to genes related to microglia functions. Based on this data, we suggest that differences between SZ and BP are due to genes involved with response to stimulus, defense response, immune system process and response to stress biological processes, all having a role in the communication of environmental factors to the cells and associated to microglia.

Molecular screening for 22Q11.2 deletion syndrome in patients with congenital heart disease.

Few studies have investigated the prevalence of 22q11.2 deletion syndrome (22q11.2DS) among patients with isolated heart defects or nonconotruncal heart defects. Polymerase chain reaction (PCR) followed by length polymorphism restriction fragment analysis (RFLP) is useful for low-cost molecular diagnosis and screening. This cross-sectional study included 392 patients with congenital heart disease, described clinical features, and performed PCR-RFLP for analysis of polymorphism in three loci with a high heterozygosity rate located in the typically deleted region of 1.5 megabases. Heterozygosity excluded 22q11.2DS. Patients with homozygosity for the three markers underwent multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) for the final diagnosis, estimating the prevalence of 22q11.2DS. The use of PCR-RFLP excluded 22q11.2DS in 81.6 % (n = 320) of 392 patients. Of the remaining 72 patients, 65 underwent MLPA, showing 22q11.2DS in five cases (prevalence, 1.27 %). Four of these five patients underwent FISH, confirming the MLPA results. All five patients with the deletion had heart diseases commonly found with 22q11.2DS (interrupted aortic arch, persistent truncus arteriosus, tetralogy of Fallot, and ventricular septal defect plus atrial septal defect). Two patients had congenital extracardiac anomaly (one with arched palate and micrognathia and one with hypertelorism). Three patients reported recurrent respiratory infections, and one patient reported hypocalcemia. All were underweight or short in stature for their age. This study contributed to showing the prevalence of 22q11.2DS in patients with any congenital heart disease, with or without other features of the syndrome. Patients with 22q11.2DS may not have all the major features of the syndrome, and those that are found may be due to the heart defect.