Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci.

Neuroblastoma is a malignant neoplasm of the developing sympathetic nervous system that is notable for its phenotypic diversity. High-risk patients typically have widely disseminated disease at diagnosis and a poor survival probability, but low-risk patients frequently have localized tumors that are almost always cured with little or no chemotherapy. Our genome-wide association study (GWAS) has identified common variants within FLJ22536, BARD1, and LMO1 as significantly associated with neuroblastoma and more robustly associated with high-risk disease. Here we show that a GWAS focused on low-risk cases identified SNPs within DUSP12 at 1q23.3 (P = 2.07 × 10⁻6), DDX4 and IL31RA both at 5q11.2 (P = 2.94 × 10⁻6 and 6.54 × 10⁻7 respectively), and HSD17B12 at 11p11.2 (P = 4.20 × 10⁻7) as being associated with the less aggressive form of the disease. These data demonstrate the importance of robust phenotypic data in GWAS analyses and identify additional susceptibility variants for neuroblastoma.

Prognostic factors for surgical outcomes among patients with multilevel cervical spondylotic myelopathy.

OBJECTIVE: Many clinical and imaging characteristics can influence the prognosis of multilevel cervical spondylotic myelopathy (M-CSM). This study investigated the factors that influence surgical outcomes among patients with M-CSM. PATIENTS AND METHODS: This prospective study included 30 patients who underwent surgical treatment for M-CSM from June 2019 to June 2021. RESULTS: The average age was 62.29 years, and the average follow-up time was 13.13 months. Preoperative, postoperative, and follow-up Modified Japanese Orthopaedic Association (mJOA) scores were 10.17, 13.53, and 16.17, respectively. The average postoperative and follow-up recovery rates were 45.46% and 76.69%, respectively. Patients older than 60 years (p = 0.04), male patients (p = 0.023), and smokers (p = 0.027) had lower preoperative mJOA scores than other groups. Patients with symptoms duration longer than 6 months had lower recovery rates (p = 0.021) than those with shorter symptom duration. Patients with intramedullary hyperintensity in ≤ 2 vertebra (p = 0.041) or anterior surgery (p = 0.022) had better postoperative recovery rates than their counterparts. A shorter period of hyperintensity in the intramedullary region on sagittal T2-weighted magnetic resonance imaging (T2W MRI) was significantly associated with faster discharge (p = 0.044). Patients with type 3 (discrete focal) hyperintensity in the intramedullary region on axial T2W MRI had a 6.75-fold increase in experiencing less than 50% postoperative recovery compared with other groups (odds ratio: 6.75, 95% confidence interval: 2.73-16.67). CONCLUSIONS: Good prognostic factors for a shorter recovery included hyperintensity in the intramedullary region for ≤ 2 levels, shorter period of hyperintensity in the intramedullary region on sagittal T2W MRI, and an anterior surgical approach. A duration of symptoms longer than 6 months and discrete hyperintensity in the intramedullary region on axial T2W MRI were poor prognostic indicators associated with a longer recovery period.

Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity.

The mechanisms underlying genetic susceptibility at loci discovered by genome-wide association study (GWAS) approaches in human cancer remain largely undefined. In this study, we characterized the high-risk neuroblastoma association at the BRCA1-related locus, BARD1, showing that disease-associated variations correlate with increased expression of the oncogenically activated isoform, BARD1ß. In neuroblastoma cells, silencing of BARD1ß showed genotype-specific cytotoxic effects, including decreased substrate-adherence, anchorage-independence, and foci growth. In established murine fibroblasts, overexpression of BARD1ß was sufficient for neoplastic transformation. BARD1ß stabilized the Aurora family of kinases in neuroblastoma cells, suggesting both a mechanism for the observed effect and a potential therapeutic strategy. Together, our findings identify BARD1ß as an oncogenic driver of high-risk neuroblastoma tumorigenesis, and more generally, they illustrate how robust GWAS signals offer genomic landmarks to identify molecular mechanisms involved in both tumor initiation and malignant progression. The interaction of BARD1ß with the Aurora family of kinases lends strong support to the ongoing work to develop Aurora kinase inhibitors for clinically aggressive neuroblastoma.