A powerful way to discover key genes playing causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here, we report high-resolution analyses of somatic copy-number alterations (SCNAs) from 3131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across multiple cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κB pathway. We show that cancer cells harboring amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend upon expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in multiple cancer types.

Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.

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Background Robot-assisted laparoscopic radical prostatectomy (RALP) has become increasingly common; however, there have been no nationwide, population-based, non–claims-based studies to evaluate differences in outcomes between RALP and open radical retropubic prostatectomy (RRP). Objective To determine surgical, oncologic, and health-related quality of life (HRQOL) outcomes following RALP and RRP in a nationwide cohort. Design, setting, and participants We identified 903 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 2000 and 2010 who underwent radical prostatectomy using RALP (n = 282) or RRP (n = 621) as primary treatment. Intervention Radical prostatectomy. Outcome measurements and statistical analysis We compared patients undergoing RALP or RRP across a range of perioperative, oncologic, and HRQOL outcomes. Results and limitations Use of RALP increased during the study period, constituting 85.2% of study subjects in 2009, up from 4.5% in 2003. Patients undergoing RALP compared to RRP were less likely to have a lymph node dissection (51.5% vs 85.4%; p < 0.0001), had less blood loss (207.4 ml vs 852.3 ml; p < 0.0001), were less likely to receive blood transfusions (4.3% vs 30.3%; p < 0.0001), and had shorter hospital stays (1.8 d vs 2.9 d; p < 0.0001). Surgical, oncologic, and HRQOL outcomes did not differ significantly among the groups. In multivariate logistic regression models, there were no significant differences in 3- or 5-yr recurrence-free survival comparing RALP versus RRP (hazard ratios: 0.98 [95% confidence interval (CI), 0.46–2.08] and 0.75 [95% CI, 0.18–3.11], respectively). Conclusions In a nationwide cohort of patients undergoing surgical treatment for prostate cancer, RALP was associated with shorter hospital stay, and lower blood loss and transfusion rates than RRP. Surgical oncologic and HRQOL outcomes were similar between groups. Patient summary We studied men throughout the United States with prostate cancer who underwent surgical removal of the prostate. We found that robot-assisted laparoscopic radical prostatectomy resulted in shorter hospital stay, less blood loss, and fewer blood transfusions than radical retropubic prostatectomy. There were no differences in cancer control or health-related quality of life.