The occurrence of colorectal cancer (CRC) is inversely correlated with estrogen receptor beta (ERβ) presence. Additionally, multiple studies associate low ERβ expression with poorer overall survival o Show more
The occurrence of colorectal cancer (CRC) is inversely correlated with estrogen receptor beta (ERβ) presence. Additionally, multiple studies associate low ERβ expression with poorer overall survival of CRC patients. Molecular pathways involved in ERβ - related reduced tumorigenesis include enhanced apoptosis, decreased proliferation, or repression of oncogenes. Moreover, the development of solid tumors, such as CRC, is often associated with an increased tumor mass that results in decreased oxygen partial tension, known as hypoxia, clinically associated with decreased prognosis and therapeutic resistance. Our high-throughput study suggests that ERβ also represses a hypoxic response in CRC cells. We observed a significantly altered transcriptional profile in HCT116 ERβ overexpressing cells that was further stimulated by E2 treatment under hypoxic conditions. The achieved data for downregulation of VEGFA, PDGFA and ANGPTL4 were validated in a time course experiment in DLD-1 cells. In addition, using an ERβ construct with a mutated DNA binding domain we observed that the downregulation of selected genes is dependent on the direct binding of this receptor to regulatory region genes. In addition, we observed that ERβ may affect the expression of the main hypoxia regulator, HIF1A, at the transcriptional and translational levels. In summary, ERβ alters the hypoxic outcome in CRC cells. Show less
Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the ext Show more
Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored. We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes. During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort. Show less