Brandon Bunker

Loss of polarity correlates with progression of epithelial cancers, but how plasma membrane misorganization drives oncogenic transcriptional events remains unclear. The polarity regulators of the Drosophila Scribble (Scrib) module are potent tumor suppressors and provide a model for mechanistic investigation. RNA profiling of Scrib mutant tumors reveals multiple signatures of neoplasia, including altered metabolism and dedifferentiation. Prominent among these is upregulation of cytokine-like Unpaired (Upd) ligands, which drive tumor overgrowth. We identified a polarity-responsive enhancer in upd3, which is activated in a coincident manner by both JNK-dependent Fos and aPKC-mediated Yki transcription. This enhancer, and Scrib mutant overgrowth in general, are also sensitive to activity of the Polycomb Group (PcG), suggesting that PcG attenuation upon polarity loss potentiates select targets for activation by JNK and Yki. Our results link epithelial organization to signaling and epigenetic regulators that control tissue repair programs, and provide insight into why epithelial polarity is tumor-suppressive.

The replication factors Cdt1 and Cdc6 are essential for origin licensing, a prerequisite for DNA replication initiation. Mechanisms to ensure that metazoan origins initiate once per cell cycle include degradation of Cdt1 during S phase and inhibition of Cdt1 by the geminin protein. Geminin depletion or overexpression of Cdt1 or Cdc6 in human cells causes rereplication, a form of endogenous DNA damage. Rereplication induced by these manipulations is however uneven and incomplete, suggesting that one or more mechanisms restrain rereplication once it begins. We find that both Cdt1 and Cdc6 are degraded in geminin-depleted cells. We further show that Cdt1 degradation in cells that have rereplicated requires the PCNA binding site of Cdt1 and the Cul4(DDB1) ubiquitin ligase, and Cdt1 can induce its own degradation when overproduced. Cdc6 degradation in geminin-depleted cells requires Huwe1, the ubiquitin ligase that regulates Cdc6 after DNA damage. Moreover, perturbations that specifically disrupt Cdt1 and Cdc6 degradation in response to DNA damage exacerbate rereplication when combined with geminin depletion, and this enhanced rereplication occurs in both human cells and in Drosophila melanogaster cells. We conclude that rereplication-associated DNA damage triggers Cdt1 and Cdc6 ubiquitination and destruction, and propose that this pathway represents an evolutionarily conserved mechanism that minimizes the extent of rereplication.

Correction to: Genetics in Medicine19:2017; https://doi.org/10.1038/gim.2017.37, published online 11 May 2017 There were errors in the author listing such that consortium group of authors was not named individually. The corrected author list is: Sienna Aguilar, MS; Swaroop Aradhya, PhD, FACMG; Daniel Beltran, PhD; Brandon Bunker, PhD; Amy Daly, MS; Anne Deucher, MD; Tali Ekstein, MS; Ali Entezam, PhD; Karl Erhard, PhD; Ed Esplin MD, PhD, FACMG, FACP; Jennifer Fulbright, MS; Amy Fuller, MS; Kristen McDonald Gibson, PhD, FACMG; Tina Hambuch, PhD, FACMG; Rachel Harte, PhD; Christy Hartshorne, MS; Eden Haverfield, PhD, FACMG; Nastaran Heidari, PhD; Michelle Hogue, MS; Daniela Iacoboni, MS; Britt Johnson, PhD, FACMG; Hio Chung Kang, PhD; Rachel Lewis, PhD; Shiloh Martin, PhD; Sarah McCalmon, PhD; Scott Michalski, MS; Cindy Morgan, MS; Laura Murillo, PhD; Piper Nicolosi, PhD; Karen Ouyang, PhD, FACMG; Carolina Pardo, PhD; Rita Quintana, PhD; Marina Rabideau, MS; Darlene Riethmaier, MS; Amanda Stafford, PhD; Jackie Tahiliani, MS; Chris Tan, MS; S. Paige Taylor, PhD; Shu-Huei Wang, PhD; Hannah White, MS; Ian Wilson, PhD, FACMG; Tom Winder, PhD, FACMG; and Michelle K. Zeman, PhD. The original article can be found online at https://doi.org/10.1038/gim.2017.37. Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteriaGenetics in MedicineVol. 19Issue 10PreviewThe 2015 American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG–AMP) guidelines were a major step toward establishing a common framework for variant classification. In practice, however, several aspects of the guidelines lack specificity, are subject to varied interpretations, or fail to capture relevant aspects of clinical molecular genetics. A simple implementation of the guidelines in their current form is insufficient for consistent and comprehensive variant classification. Full-Text PDF Open Access

Pituitary metastasis is a rare manifestation of systemic malignancy accounting for approximately 1% of all pituitary tumors. Breast and lung tumors are the most common primary sources of metastases, yet other sites such as the gastrointestinal tract, prostate, kidney, thyroid, and pancreas have also been reported. The vast majority of pituitary metastasis are clinically silent; however, the most common presenting symptoms are usually related to pituitary dysfunction, with posterior pituitary predominance, as well as visual field defects secondary to mass effect. We present two cases of pituitary metastases, both middle-aged adult females with an extensive history of tobacco use presenting with new onset headaches and visual disturbances. The first case with pituitary metastasis as the first manifestation of underlying small cell lung carcinoma, and the second case with known metastatic small cell lung carcinoma receiving combination therapy with chemotherapy and immunotherapy who was found to have pituitary involvement. Both cases exhibited signs and symptoms of pituitary dysfunction requiring hormonal replacement therapy. Pituitary metastasis is a rare condition and often remains undiagnosed. Most metastatic tumors to the pituitary are clinically silent and diagnosed incidentally, and in many cases carries a poor prognosis. Distinguishing pituitary metastasis from other pituitary lesions based on clinical presentation and radiologic features is often challenging due to clinical and radiologic findings often being nonspecific, therefore a high index of clinical suspicion and physician awareness is of paramount importance. Management of pituitary metastasis may include surgery and radiotherapy, as well as, chemotherapy, immunotherapy and hormonal therapy, but evidence on the outcomes of these approaches is limited.