Genomic attributes of homology-directed DNA repair deficiency in metastatic prostate cancer.

Cancers with homology-directed DNA repair (HRR) deficiency exhibit high response rates to poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy. Though mutations disrupting BRCA1 and BRCA2 associate with HRR deficiency (HRRd), patterns of genomic aberrations and mutation signatures may be more sensitive and specific indicators of compromised repair. Here, we evaluated whole-exome sequences from 418 metastatic prostate cancers (mPCs) and determined that one-fifth exhibited genomic characteristics of HRRd that included Catalogue Of Somatic Mutations In Cancer mutation signature 3. Notably, a substantial fraction of tumors with genomic features of HRRd lacked biallelic loss of a core HRR-associated gene, such as BRCA2. In this subset, HRRd associated with loss of chromodomain helicase DNA binding protein 1 but not with mutations in serine-protein kinase ATM, cyclin dependent kinase 12, or checkpoint kinase 2. HRRd genomic status was strongly correlated with responses to PARPi and platinum chemotherapy, a finding that supports evaluating biomarkers reflecting functional HRRd for treatment allocation.

Gene expression profile associated with postnatal development of pyramidal neurons in the human prefrontal cortex implicates ubiquitin ligase E3 in the pathophysiology of schizophrenia onset.

Schizophrenia is a neurodevelopmental disorder with the typical age of onset of overt symptoms and deficits occurring during late adolescence or early adulthood, coinciding with the final maturation of the cortical network involving the prefrontal cortex. These observations have led to the hypothesis that disturbances of the developmental events that take place in the prefrontal cortex during this period, specifically the remodeling of synaptic connectivities between pyramidal neurons, may contribute to the onset of illness. In this context, we investigated the gene expression changes of pyramidal neurons in the human prefrontal cortex during normal periadolescent development in order to gain insight into the possible molecular mechanisms involved in synaptic remodeling of pyramidal neuronal circuitry. Our data suggest that genes associated with the ubiquitination system, which has been implicated in the biology of synaptic plasticity, may play a major role. Among these genes, UBE3B, which encodes the ubiquitin ligase E3, was found to undergo periadolescent increase and was validated at the protein level to be upregulated during periadolescent development. Furthermore, we found that the density of UBE3B-immunoreactive pyramidal neurons was decreased in schizophrenia subjects, consistent with the result of a previous study of decreased UBE3B mRNA expression in pyramidal neurons in this illness. Altogether these findings point to the novel hypothesis that this specific ligase may play a role in the developmental pathogenesis of schizophrenia onset by possibly altering the synaptic remodeling process.