Search

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing. [ABSTRACT FROM AUTHOR]

Objective: We tested the hypothesis that the three clinical phenotypes of polycystic ovary syndrome (PCOS) represent forms of the same metabolic disorder. Design: Prospective cohort analysis. Setting: University-based tertiary care. Patient(s): Three-hundred sixteen untreated consecutive women diagnosed as having PCOS. Intervention(s): None. Main Outcome Measure(s): Each subject underwent an evaluation of ovulatory function, body habitus, acne, and hirsutism; serum free and total testosterone (T), 17-hydroxyprogesterone (17-HP), and DHEAS; and fasting plasma glucose and insulin levels. Insulin resistance and β-cell function were assessed using the homeostatic assessment model equation (HOMA-IR and HOMA-β-cell, respectively). Result(s): The Oligo+HA+Hirsutism phenotype was present in 48% of subjects, Oligo+HA in 29%, and Oligo+Hirsutism in 23%. The three phenotypes did not differ in mean body mass index, waist-to-hip ratio, racial composition, degree of oligo-ovulation, prevalence of acne, or family history of hyperandrogenic symptomatology. However, subjects demonstrating the Oligo+HA+Hirsutism phenotype were the youngest and had the greatest degrees of hyperandrogenemia, hyperinsulinemia, and β-cell function; patients with the Oligo+Hirsutism phenotype where the oldest and had the mildest degrees of hyperandrogenemia, hyperinsulinemia, and β-cell function. Subjects with the Oligo+HA phenotype demonstrated intermediate degrees of hyperandrogenemia and metabolic dysfunction. Conclusion(s): We conclude that the three clinical phenotypes of PCOS do not represent forms of the same metabolic disorder and may be the result of varying degrees of metabolic dysfunction; greater degrees of β-cell function and circulating insulin levels favored the development of hirsutism and frank hyperandrogenemia. [Copyright &y& Elsevier]