Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent ...mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.
Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we ...perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.
The Gleason score is the best independent predictor of prostate cancer outcomes.1 The principle distinction between Gleason 6 disease vs Gleason 7 to 10 disease is that Gleason 6 disease does not ...necessarily need definitive treatment.2 Nevertheless, the implications of Gleason score are less clear in black men because of disparate prostate cancer outcomes, particularly for Gleason 6 disease, in which risk assessment and management of disease in black men is controversial.2,3 We investigated prostate cancer–specific mortality by Gleason score and race.
At the health systems level, lack of diagnostic ability, inadequate access to trained providers, and limited drug availability provide significant barriers to cancer care delivery. This article ...outlines an urgent call to action to improve access to precision oncology therapies in lower‐ and middle‐income countries, drawing upon lessons from international efforts in oncology and infectious disease.
Larotrectinib is a small-molecule kinase inhibitor that targets NTRK fusions that occur in multiple types of cancer. Its FDA approval represents the first instance of a treatment indication being ...designated “tumor-agnostic” from the outset, being based on actionable genomic insights. To view this Bench to Bedside, open or download the PDF.
Larotrectinib is a small-molecule kinase inhibitor that targets NTRK fusions that occur in multiple types of cancer. Its FDA approval represents the first instance of a treatment indication being designated “tumor-agnostic” from the outset, being based on actionable genomic insights. To view this Bench to Bedside, open or download the PDF.
The study by Jaratlerdsiri and colleagues represents the first whole-genome sequencing study of prostate cancer from men in sub-Saharan Africa. Preliminary findings include a higher tumor mutation ...burden in these tumors compared with data from other available prostate cancer cohorts. Although larger studies are needed and greater effort and investment to include patients of African ancestry in cancer genomic studies overall, the findings begin to catalog the diversity of prostate cancer genomics in the African population, which has a high burden of disease and mortality from prostate cancer.
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In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer ...Project, we calculated telomere content across 1299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.
Systemic iron balance is regulated by hepcidin, a peptide hormone secreted by the liver. By decreasing cell surface expression of the iron exporter ferroportin, hepcidin decreases iron absorption ...from the intestine and iron release from reticuloendothelial stores. Hepcidin excess has been implicated in the pathogenesis of anemia of chronic disease, while hepcidin deficiency has a key role in the pathogenesis of the iron overload disorder hemochromatosis. We have recently shown that hemojuvelin is a coreceptor for bone morphogenetic protein (BMP) signaling and that BMP signaling positively regulates hepcidin expression in liver cells in vitro. Here we show that BMP-2 administration increases hepcidin expression and decreases serum iron levels in vivo. We also show that soluble hemojuvelin (HJV.Fc) selectively inhibits BMP induction of hepcidin expression in vitro and that administration of HJV.Fc decreases hepcidin expression, increases ferroportin expression, mobilizes splenic iron stores, and increases serum iron levels in vivo. These data support a role for modulators of the BMP signaling pathway in treating diseases of iron overload and anemia of chronic disease.
Background
Significant racial disparities in prostate cancer incidence and mortality have been reported between African American Men (AAM), who are at increased risk for prostate cancer, and European ...American Men (EAM). In most of the studies carried out on prostate cancer, this population is underrepresented. With the advancement of genome‐wide association studies, several genetic predictor models of prostate cancer risk have been elaborated, as well as numerous studies that identify both germline and somatic mutations with clinical utility.
Recent Findings
Despite significant advances, the AAM population continues to be underrepresented in genomic studies, which can limit generalizability and potentially widen disparities. Here we outline racial disparities in currently available genomic applications that are used to estimate the risk of individuals developing prostate cancer and to identify personalized oncology treatment strategies. While the incidence and mortality of prostate cancer are different between AAM and EAM, samples from AAM remain to be unrepresented in different studies.
Conclusion
This disparity impacts the available genomic data on prostate cancer. As a result, the disparity can limit the predictive utility of the genomic applications and may lead to the widening of the existing disparities. More studies with substantially higher recruitment and engagement of African American patients are necessary to overcome this disparity.
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