Functionally Validating Evolutionary Conserved Risk Genes for Parkinson's Disease in Drosophila melanogaster.

Parkinson's disease (PD) is a heterogeneous and complex neurodegenerative disorder and large-scale genetic studies have identified >130 genes associated with PD. Although genomic studies have been decisive for our understanding of the genetic contributions underlying PD, these associations remain as statistical associations. Lack of functional validation limits the biological interpretation; however, it is labour extensive, expensive, and time consuming. Therefore, the ideal biological system for functionally validating genetic findings must be simple. The study aim was to assess systematically evolutionary conserved PD-associated genes using Drosophila melanogaster. From a literature review, a total of 136 genes have found to be associated with PD in GWAS studies, of which 11 are strongly evolutionary conserved between Homo sapiens and D. melanogaster. By ubiquitous gene expression knockdown of the PD-genes in D. melanogaster, the flies' escape response was investigated by assessing their negative geotaxis response, a phenotype that has previously been used to investigate PD in D. melanogaster. Gene expression knockdown was successful in 9/11 lines, and phenotypic consequences were observed in 8/9 lines. The results provide evidence that genetically modifying expression levels of PD genes in D. melanogaster caused reduced climbing ability of the flies, potentially supporting their role in dysfunctional locomotion, a hallmark of PD.

Circulating Tumor DNA in Patients with Renal Cell Carcinoma. A Systematic Review of the Literature.

CONTEXT: Over the past decade there has been increasing interest in the potential of liquid biopsies and systematic biomarkers in the diagnosis and management of kidney cancer, as they may provide a tool for early detection of disease and monitoring of treatment response. OBJECTIVE: To identify and summarize relevant published data on circulating tumor DNA (ctDNA) in patients with renal cell carcinoma (RCC). EVIDENCE ACQUISITION: We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement of studies identified in PubMed, MEDLINE, EMBASE, and Cochrane Library up to January 15, 2021. Two reviewers independently screened all articles and performed the data extraction. EVIDENCE SYNTHESIS: Nineteen studies investigating ctDNA in RCC (1237 patients) were included and analyzed in the final review. The study size and design varied widely, and the studies were divided into five groups according to the method used for ctDNA detection. The outcome data included (1) the sensitivity/specificity if available; (2) the method used for ctDNA detection; and (3) the main findings in the studies. CONCLUSIONS: The studies highlight that the level of ctDNA in RCC appears to be low. Studies using multiple methods for ctDNA detection indicate that tumor-guided analysis improves the ctDNA detection rate and suggest that cell-free methylated DNA immunoprecipitation and high-throughput sequencing may be a very sensitive method for ctDNA detection in RCC. PATIENT SUMMARY: We systematically reviewed the literature to identify all relevant studies investigating circulating tumor DNA in patients with kidney cancer to investigate its use and potential in this highly malignant disease. We found that the level of circulating tumor DNA is low in kidney cancer and that very sensitive methods have to be used for detection in this disease.

Epithelial ovarian cancer and the use of circulating tumor DNA: A systematic review.

OBJECTIVE: One way to improve the survival rate of epithelial Ovarian Cancer (EOC) is by identifying effective biomarkers useful at different stages and time points of the disease. A potential biomarker is circulating tumor DNA (ctDNA) in plasma or serum. In this systematic review, we provide an overview of applications of ctDNA in EOC to discuss the direction of future research in this field. METHODS: We performed a systematic search in Pubmed, Embase, and Scopus to identify relevant clinical studies eligible for inclusion. Furthermore, the references in the identified studies and relevant reviews were assessed to identify additional studies. The PRISMA guideline was employed to perform the systematic review, and data from the studies were extracted using piloted data extraction forms. RESULTS: A total of 36 observational studies were included. The concordance between tumor and ctDNA was assessed in 19 studies, early diagnosis in 1, diagnosis in 23, monitoring of treatment response in 7, detection of reversion mutations in 3, prognosis in 9, but no studies assessed early detection of recurrence. Data from the studies were reported descriptively. The studies had a large variation in the methods used for ctDNA analysis and limited sample sizes of 10-126 patients. Overall, the studies show that ctDNA is a potential biomarker for EOC useful in several settings during assessment and treatment of these patients. CONCLUSIONS: Although the identified studies are limited in number and their methods for ctDNA analysis vary, it is clear that ctDNA as a biomarker for EOC is promising for several applications in diagnostics, monitoring of treatment response, and prognostics. However, more studies are needed to establish the ideal methods and settings for the clinical use of ctDNA in EOC.

Polygenic Risk Score Prediction for Endometriosis.

Endometriosis is a major health care challenge because many young women with endometriosis go undetected for an extended period, which may lead to pain sensitization. Clinical tools to better identify candidates for laparoscopy-guided diagnosis are urgently needed. Since endometriosis has a strong genetic component, there is a growing interest in using genetics as part of the clinical risk assessment. The aim of this work was to investigate the discriminative ability of a polygenic risk score (PRS) for endometriosis using three different cohorts: surgically confirmed cases from the Western Danish endometriosis referral Center (249 cases, 348 controls), cases identified from the Danish Twin Registry (DTR) based on ICD-10 codes from the National Patient Registry (140 cases, 316 controls), and replication analysis in the UK Biobank (2,967 cases, 256,222 controls). Patients with adenomyosis from the DTR (25 cases) and from the UK Biobank (1,883 cases) were included for comparison. The PRS was derived from 14 genetic variants identified in a published genome-wide association study with more than 17,000 cases. The PRS was associated with endometriosis in surgically confirmed cases [odds ratio (OR) = 1.59, p = 2.57× 10-7] and in cases from the DTR biobank (OR = 1.50, p = 0.0001). Combining the two Danish cohorts, each standard deviation increase in PRS was associated with endometriosis (OR = 1.57, p = 2.5× 10-11), as well as the major subtypes of endometriosis; ovarian (OR = 1.72, p = 6.7× 10-5), infiltrating (OR = 1.66, p = 2.7× 10-9), and peritoneal (OR = 1.51, p = 2.6 × 10-3). These findings were replicated in the UK Biobank with a much larger sample size (OR = 1.28, p < 2.2× 10-16). The PRS was not associated with adenomyosis, suggesting that adenomyosis is not driven by the same genetic risk variants as endometriosis. Our results suggest that a PRS captures an increased risk of all types of endometriosis rather than an increased risk for endometriosis in specific locations. Although the discriminative accuracy is not yet sufficient as a stand-alone clinical utility, our data demonstrate that genetics risk variants in form of a simple PRS may add significant new discriminatory value. We suggest that an endometriosis PRS in combination with classical clinical risk factors and symptoms could be an important step in developing an urgently needed endometriosis risk stratification tool.

Tumor-specific genetic aberrations in cell-free DNA of gastroesophageal cancer patients.

The applicability of liquid biopsies is studied intensively in all types of cancer and analysis of circulating tumor DNA (ctDNA) has recently been implemented clinically for mutation detection in lung cancer. ctDNA may provide information about tumor quantity and mutations present in the tumor, and as such have many potential applications in diagnosis and treatment of cancer. It has been suggested that ctDNA analysis may overcome the issue of intra-tumor heterogeneity faced by tissue biopsies and serve as an additional diagnostic tool. Furthermore, liquid biopsies are potentially helpful for monitoring of treatment response as well as detection of minimal residual disease and relapse. Gastroesophageal cancers (GEC) have high mortality rates and the majority of patients present with advanced stage at diagnosis or succumb due to disease recurrence even after radical resection of the primary tumor. Biomarkers that can help optimize treatment strategy are thus highly desirable. The present study is a review of published data on ctDNA in GEC patients. We identified 25 studies in which tumor-specific genetic aberrations were investigated in plasma or serum and discuss these in relation to the methods applied for ctDNA analysis. The methods used for ctDNA detection greatly influence the sensitivity of the analysis and, therefore, the potential clinical applications. We found that studies of ctDNA in GEC, although limited in number, are promising for several applications such as genetic profiling of tumors and monitoring of disease progression. However, more studies are needed to establish if and how this analysis can be clinically implemented.