Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

Tumor size predicts vascular invasion and histologic grade: Implications for selection of surgical treatment for hepatocellular carcinoma

Vascular invasion and high histologic grade predict poor outcome after surgical resection or liver transplantation for hepatocellular carcinoma (HCC). Despite the known association between tumor size and vascular invasion, a proportion of patients with large tumors can be treated surgically with excellent outcomes. Clarification of the association between tumor size, histologic grade, and vascular invasion has implications for patient selection for resection and transplantation. The objective of this study was to examine the relationship between HCC tumor size and microscopic (occult) vascular invasion and histologic grade in a multicenter international database of 1,073 patients who underwent resection of HCC. The incidence of microscopic vascular invasion increased with tumor size (≤3 cm, 25%; 3.1-5 cm, 40%; 5.1-6.5 cm, 55%; >6.5 cm, 63%) (P < 0.005). Both size and number of tumors were important factors predicting vascular invasion. Among all patients with tumors 5.1 to 6.5 cm, microscopic vascular invasion was present in 55% compared with 31% for all patients with tumors 5 cm or smaller (P < 0.001). Among patients with solitary tumors only, microscopic vascular invasion was significantly more common in tumors measuring 5.1 to 6.5 cm (41%) compared with 27% of tumors 5 cm or smaller (P < 0.003). Tumor size also predicted histologic grade: 36% of tumors 5 cm or smaller were high grade, compared with 54% of lesions 5.1 to 6.5 cm. (P = 0.01). High histologic grade, an alpha-fetoprotein level of at least 1000 ng/mL, and multiple tumor nodules each predicted occult vascular invasion in tumors larger than 5 cm. The high incidence of occult vascular invasion and advanced histologic grade in HCC tumors larger than 5 cm, as well as biologic predictors of poor prognosis, should be considered before criteria for transplantation are expanded to include these patients. Copyright © 2005 by the American Association for the Study of Liver Diseases.link_to_subscribed_fulltex