Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions.

The spatiotemporal program of metazoan DNA replication is regulated during development and altered in cancers. We have generated novel OK-seq, Repli-seq and RNA-seq data to compare the DNA replication and gene expression programs of twelve cancer and non-cancer human cell types. Changes in replication fork directionality (RFD) determined by OK-seq are widespread but more frequent within GC-poor isochores and largely disconnected from transcription changes. Cancer cell RFD profiles cluster with non-cancer cells of similar developmental origin but not with different cancer types. Importantly, recurrent RFD changes are detected in specific tumour progression pathways. Using a model for establishment and early progression of chronic myeloid leukemia (CML), we identify 1027 replication initiation zones (IZs) that progressively change efficiency during long-term expression of the BCR-ABL1 oncogene, being twice more often downregulated than upregulated. Prolonged expression of BCR-ABL1 results in targeting of new IZs and accentuation of previous efficiency changes. Targeted IZs are predominantly located in GC-poor, late replicating gene deserts and frequently silenced in late CML. Prolonged expression of BCR-ABL1 results in massive deletion of GC-poor, late replicating DNA sequences enriched in origin silencing events. We conclude that BCR-ABL1 expression progressively affects replication and stability of GC-poor, late-replicating regions during CML progression.

Invasive aspergillosis in patients with hematologic malignancies: incidence and description of 127 cases enrolled in a single institution prospective survey from 2004 to 2009.

BACKGROUND: The study objectives were: 1) to report on invasive aspergillosis patients in a hematology department; and 2) to estimate its incidence according to the hematologic diagnosis. DESIGN AND METHODS: A prospective survey of invasive aspergillosis cases was undertaken between January 2004 and December 2009 in the hematology department of a university hospital. Meetings with clinicians, mycologists and infection control practitioners were organized monthly to confirm suspected aspergillosis cases. Demographic characteristics, clinical and complementary examination results were recorded prospectively. Information on hospitalization was extracted from administrative databases. Invasive aspergillosis diagnosis followed the European Organization for Research and Treatment of Cancer criteria, and proven and probable IA cases were retained. A descriptive analysis was conducted with temporal trends of invasive aspergillosis incidence assessed by adjusted Poisson regression. RESULTS: Overall, 4,073 hospitalized patients (78,360 patient-days) were included in the study. In total, 127 (3.1%) patients presented invasive aspergillosis. The overall incidence was 1.6 per 1,000 patient-days (95% confidence interval: 1.4, 1.9) with a decrease of 16% per year (-1%, -28%). The incidence was 1.9 per 1,000 patient-days (1.5, 2.3) in acute myeloid leukemia patients with a decrease of 20% per year (-6%, -36%). Serum Aspergillus antigen was detected in 89 (71%) patients; 29 (23%) had positive cultures, and 118 (93%), abnormal lung CT scans. One-month mortality was 13%; 3-month mortality was 42%. Mortality tended to decrease between 2004 and 2009. CONCLUSIONS: Invasive aspergillosis incidence and mortality declined between 2004 and 2009. Knowledge of invasive aspergillosis characteristics and its clinical course should help to improve the management of these patients with severe disease.