Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers.

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. SIGNIFICANCE: Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.

Single Nucleotide Polymorphisms and Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-Analysis of the Literature.

STUDY DESIGN: Meta-analysis. OBJECTIVE: To determine the single nucleotide polymorphisms (SNPs) that are related to adult idiopathic scoliosis. SUMMARY AND BACKGROUND DATA: Adolescent idiopathic scoliosis (AIS) is considered one of the most prevalent spinal diseases. Even though the cause of AIS is yet to be determined, family history and sex have shown conclusive associations. Multiple studies have indicated that AIS is more prevalent in families where at least one other first-degree relative is similarly affected, indicating a possible genetic etiology to AIS. MATERIALS AND METHODS: Articles were collected from 3 different search engines and then processed in 2 stages for final article selection for quantitative analysis. Five different genetic models were represented to show the association between the different SNPs and AIS. The Hardy-Weinberg equilibrium was examined using Fisher exact test, with significance set at P <0.05. The final analysis paper's quality was evaluated using the Newcastle Ottawa Scale. Kappa interrater agreement was calculated to evaluate the agreement between authors. RESULTS: The final analysis comprised 43 publications, 19412 cases, 22005 controls, and 25 distinct genes. LBX1 rs11190870 T>C and MATN-1 SNPs were associated with an increased risk of AIS in one or all of the 5 genetic models. IGF-1 , estrogen receptor alfa, and MTNR1B , SNPs were not associated with AIS in all 5 genetic models. Newcastle Ottawa Scale showed good quality for the selected articles. Cohen k = 0.741 and Kappa interrater agreement of 84% showed that the writers were in strong agreement. CONCLUSIONS: There seem to be associations between AIS and genetic SNP. Further larger studies should be conducted to validate the results.

Folate Pathway Gene Single Nucleotide Polymorphisms and Neural Tube Defects: A Systematic Review and Meta-Analysis.

Neural tube defects (NTDs) are congenital abnormalities in the central nervous system. The exact etiology of NTDs is still not determined, but several genetic and epigenetic factors have been studied. Folate supplementation during gestation is recommended to reduce the risk of NTDs. In this review we examine single nucleotide polymorphisms (SNPs) of the genes in the folate pathway associated with NTD. We reviewed the literature for all papers discussing both NTDs and SNPs in the folate pathway. Data were represented through five different genetic models. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS) and Cohen's Kappa inter-rater coefficient assessed author agreement. Fifty-nine papers were included. SNPs in MTHFR, MTRR, RFC genes were found to be highly associated with NTD risk. NOS showed that high quality papers were selected, and Kappa Q-test was 0.86. Our combined results support the notion that SNPs significantly influence NTDs across the population, particularly in Asian ethnicity. Additional high-quality research from diverse ethnicities is needed and meta-regression analysis based on a range of criteria may provide a more complete understanding of the role of folate metabolism in NTDs.