Do Psychiatric Disorders Influence the Risk of Female Cancer? Results From a Genetic Study

2020 ◽  
Author(s):  
Jingjing Zhu ◽  
Haoyu Zhang ◽  
Zheng Niu ◽  
Jing Song ◽  
Xia Jiang
Keyword(s):  
Breast Cancer ◽  
Mental Health ◽  
Association Studies ◽  
Health Condition ◽  
Poor Mental Health ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Depression And Anxiety ◽  
Genome Wide ◽  
Deleterious Consequence

Abstract Background: Depression and anxiety contribute to an increased global burden of disease and affect women more often than men. Despite evidence from experimental data showing a shared biological mechanism involved in both mental health disorders and female hormone-dependent cancers, results from epidemiological investigations remain inconsistent.Methods: We aim to understand a putative causal relationship between psychological distress and female malignancy by conducting a two-sample Mendelian randomization (MR) analysis. We used summary statistics from the hitherto largest genome-wide association studies (GWAS) performed in depression (Ncase=246,363), anxiety (Ncase=44,465), breast (Ncase=122,977) and ovarian (Ncase=25,509) cancer. We constructed strong instruments using the 102 depression-associated SNPs, the 6 anxiety-associated SNPs, and applied several MR approaches.Results: We found that genetic predisposition to depression significantly increased the risk of both overall breast cancer (OR [95%CI] = 1.10 [1.03-1.18]) and its estrogen receptor (ER)- subtype (1.12 [1.01-1.24]), while a borderline significance was observed for ER+ subtype (1.08 [0.99-1.18]). These findings were corroborated by our genetic correlation analysis where a significantly shared genetic basis was observed for depression and breast cancer. On the contrary, we did not identify any causal association of anxiety with breast cancer. None of the mental health traits were associated with the onset of ovarian cancer or its serous subtype. Sensitivity analyses using different sets of instruments revealed consistent results.Conclusions: Our findings suggest that poor mental health condition such as major depression disorder is likely to be causally associated with the development of breast cancer, providing evidence supporting for the potential deleterious consequence of mental illness on cancer onset.

scholarly journals Critical Analysis of Genome-Wide Association Studies: Triple Negative Breast Cancer Quae Exempli Causa

2020 ◽  
Vol 21 (16) ◽  
pp. 5835
Author(s):  
Maria-Ancuta Jurj ◽  
Mihail Buse ◽  
Alina-Andreea Zimta ◽  
Angelo Paradiso ◽  
Schuyler S. Korban ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Genetic Risk ◽  
Triple Negative ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Breast Cancer Susceptibility ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genome Wide

Genome-wide association studies (GWAS) are useful in assessing and analyzing either differences or variations in DNA sequences across the human genome to detect genetic risk factors of diseases prevalent within a target population under study. The ultimate goal of GWAS is to predict either disease risk or disease progression by identifying genetic risk factors. These risk factors will define the biological basis of disease susceptibility for the purposes of developing innovative, preventative, and therapeutic strategies. As single nucleotide polymorphisms (SNPs) are often used in GWAS, their relevance for triple negative breast cancer (TNBC) will be assessed in this review. Furthermore, as there are different levels and patterns of linkage disequilibrium (LD) present within different human subpopulations, a plausible strategy to evaluate known SNPs associated with incidence of breast cancer in ethnically different patient cohorts will be presented and discussed. Additionally, a description of GWAS for TNBC will be presented, involving various identified SNPs correlated with miRNA sites to determine their efficacies on either prognosis or progression of TNBC in patients. Although GWAS have identified multiple common breast cancer susceptibility variants that individually would result in minor risks, it is their combined effects that would likely result in major risks. Thus, one approach to quantify synergistic effects of such common variants is to utilize polygenic risk scores. Therefore, studies utilizing predictive risk scores (PRSs) based on known breast cancer susceptibility SNPs will be evaluated. Such PRSs are potentially useful in improving stratification for screening, particularly when combining family history, other risk factors, and risk prediction models. In conclusion, although interpretation of the results from GWAS remains a challenge, the use of SNPs associated with TNBC may elucidate and better contextualize these studies.

scholarly journals Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers

2013 ◽  
Vol 34 (7) ◽  
pp. 1520-1528 ◽  
Author(s):  
Y. Zheng ◽  
T. O. Ogundiran ◽  
A. G. Falusi ◽  
K. L. Nathanson ◽  
E. M. John ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fine Mapping ◽  
Association Studies ◽  
African Ancestry ◽  
Cancer Genome ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

A combined analysis of genome-wide association studies in breast cancer

2010 ◽  
Vol 126 (3) ◽  
pp. 717-727 ◽  
Author(s):  
Jingmei Li ◽  
Keith Humphreys ◽  
Tuomas Heikkinen ◽  
Kristiina Aittomäki ◽  
Carl Blomqvist ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Combined Analysis ◽  
Genome Wide

scholarly journals A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Darrell L. Ellsworth ◽  
Clesson E. Turner ◽  
Rachel E. Ellsworth
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Large Scale ◽  
Triple Negative ◽  
Association Studies ◽  
African Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Elements ◽  
Genome Wide ◽  
Increased Risk

Triple negative breast cancer (TNBC), representing 10-15% of breast tumors diagnosed each year, is a clinically defined subtype of breast cancer associated with poor prognosis. The higher incidence of TNBC in certain populations such as young women and/or women of African ancestry and a unique pathological phenotype shared between TNBC and BRCA1-deficient tumors suggest that TNBC may be inherited through germline mutations. In this article, we describe genes and genetic elements, beyond BRCA1 and BRCA2, which have been associated with increased risk of TNBC. Multigene panel testing has identified high- and moderate-penetrance cancer predisposition genes associated with increased risk for TNBC. Development of large-scale genome-wide SNP assays coupled with genome-wide association studies (GWAS) has led to the discovery of low-penetrance TNBC-associated loci. Next-generation sequencing has identified variants in noncoding RNAs, viral integration sites, and genes in underexplored regions of the human genome that may contribute to the genetic underpinnings of TNBC. Advances in our understanding of the genetics of TNBC are driving improvements in risk assessment and patient management.

scholarly journals FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women

2010 ◽  
Vol 31 (8) ◽  
pp. 1417-1423 ◽  
Author(s):  
Jill S. Barnholtz-Sloan ◽  
Priya B. Shetty ◽  
Xiaowei Guan ◽  
Sarah J. Nyante ◽  
Jingchun Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
African American ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Younger Women ◽  
Genome Wide

scholarly journals CRISPR screens identify gene targets and drug repositioning opportunities at breast cancer risk loci

2021 ◽  
Author(s):  
Natasha K Tuano ◽  
Jonathan Beesley ◽  
Murray Manning ◽  
Wei Shi ◽  
Luis Malver-Ortega ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Drug Repositioning ◽  
Association Studies ◽  
Drug Repurposing ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Causal Variants ◽  
Cancer Phenotypes

Genome-wide association studies (GWAS) have identified >200 loci associated with breast cancer (BC) risk. The majority of candidate causal variants (CCVs) are in non-coding regions and are likely to modulate cancer risk by regulating gene expression. We recently developed a scoring system, INQUISIT, to predict candidate risk genes at BC-risk loci. Here, we used pooled CRISPR activation and suppression screens to validate INQUISIT predictions, and to define the cancer phenotypes they mediate. We measured proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on the DNA damage response. We performed 60 CRISPR screens and identified 21 high-confidence INQUISIT predictions that mediate a cancer phenotype. We validated the direct regulation of a subset of genes by BC-risk variants using HiCHIP and CRISPRqtl. Furthermore, we show the utility of expression profiling for drug repurposing against these targets. We provide a platform for identifying gene targets of risk variants, and lay a blueprint of interventions for BC risk reduction and treatment.

scholarly journals Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer

2017 ◽  
Author(s):  
Knut M. Wittkowski ◽  
Christina Dadurian ◽  
Martin P. Seybold ◽  
Han Sang Kim ◽  
Ayuko Hoshino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Animal Studies ◽  
Association Studies ◽  
Treatment Options ◽  
Cell Cycle Control ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Estrogen Receptor Positive

AbstractMost breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600–2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance.Results from three independent GWAS of 1000–2000 subjects each, which were made available under the National Institute of Health’s “Up For A Challenge” (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids via alpha-cyclodextrins (αCD) as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of β1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells).Beta-cyclodextrins (βCD) have already been shown to be effective inin vitroand animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller αCDs also scavenges phospholipids, but cannot fit cholesterol. Anin-vitrostudy presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPβCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer.If the previous successful animal studies with βCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triplenegative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

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