Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers.

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

MicroRNAs in kidney development and disease.

MicroRNAs (miRNAs) belong to a class of endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, through both translational repression and mRNA destabilization. They are key regulators of kidney morphogenesis, modulating diverse biological processes in different renal cell lineages. Dysregulation of miRNA expression disrupts early kidney development and has been implicated in the pathogenesis of developmental kidney diseases. In this Review, we summarize current knowledge of miRNA biogenesis and function and discuss in detail the role of miRNAs in kidney morphogenesis and developmental kidney diseases, including congenital anomalies of the kidney and urinary tract and Wilms tumor. We conclude by discussing the utility of miRNAs as potentially novel biomarkers and therapeutic agents.

Epidemiology and prognostic factors of pediatric brain tumor survival in the US: Evidence from four decades of population data.

Brain tumors, a group of heterogeneous diseases, are the second most common cancer and the leading cause of cancer-related deaths in children. Insight into the prognosis of pediatric brain tumor survival has led to improved outcomes and could be further advanced through precision in prognosis. We analyzed the United States SEER population-based dataset of 15,723 pediatric brain tumor patients diagnosed and followed between 1975 and 2016 using a stratified Cox proportional hazards model. Mortality risk declined with increased age at diagnosis, the adjusted hazard ratio (aHR) (95 % confidence interval) was 0.60 (0.55, 0.67) and 0.47 (0.42, 0.52) for ages at diagnosis 1-10 years and 10-19 years, respectively, when compared with infants. Non-Hispanic Caucasian patients showed a lower risk of mortality than non-Hispanic African Americans (1.21 (1.11, 1.32)) and Hispanics (1.21 (1.11, 1.32)). Primary tumor sites, grades, and histology showed substantial heterogeneity in mortality risk. Brainstem (2.62 (2.41, 2.85)) and Cerebrum (1.63 (1.46, 1.81)) had an elevated risk of mortality than lobes. Similarly, Grade II (1.32 (1.07, 1.62)), Grade III (3.39 (2.74, 4.19)), and Grade IV (2.18 (1.80, 2.64)) showed an inflated risk of mortality than Grade I. Compared to low-grade glioma, high-grade glioma (7.92 (7.09, 8.85)), Primitive neuroectodermal tumors (4.72 (4.15, 5.37)), Medulloblastoma (3.11 (2.79, 3.47)), and Ependymal-tumors (2.20 (1.95, 2.48)) had increased risk of mortality. County-level poverty and geographic region showed substantial variation in survival. This large population-based comprehensive study confirmed identified prognostic factors of pediatric brain tumor survival and provided estimates as epidemiologic evidence with greater generalization.