Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila tumor suppressor-related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo, by normally binding β-catenin and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis, and impacts patient survival. Together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis. These findings unify two outstanding questions in cancer biology: the basis of Wnt activation in non-colorectal tumors, and the identity of a 4q35 tumor suppressor.

Recent findings implicate embryonic signaling centers in patterning the mammalian cerebral cortex. We used mouse in utero electroporation and mutant analysis to test whether cortical signaling sources interact to regulate one another. We identified interactions between the cortical hem, rich in Wingless-Int (WNT) proteins and bone morphogenetic proteins (BMPs), and an anterior telencephalic source of fibroblast growth factors (FGFs). Expanding the FGF8 domain suppressed Wnt2b, Wnt3a and Wnt5a expression in the hem. Next to the hem, the hippocampus was shrunken, consistent with its dependence for growth on a hem-derived WNT signal. Maintenance of hem WNT signaling and hippocampal development thus require a constraint on the FGF8 source, which is likely to be supplied by BMP activity. When endogenous BMP signaling is inhibited by noggin, robust Fgf8 expression appears ectopically in the cortical primordium. Abnormal signaling centers were further investigated in mice lacking the transcription factor EMX2, in which FGF8 activity is increased, WNT expression reduced, and the hippocampus defective. Suggesting that these defects are causally related, sequestering FGF8 in Emx2 homozygous mutants substantially recovered WNT expression in the hem and partially rescued hippocampal development. Because noggin can induce Fgf8 expression, we examined noggin and BMP signaling in the Emx2 mutant. As the telencephalic vesicle closed, Nog expression was expanded and BMP activity reduced,potentially leading to FGF8 upregulation. Our findings point to a cross-regulation of BMP, FGF, and WNT signaling in the early telencephalon,integrated by EMX2, and required for normal cortical development.

Activation of the PI3K and epidermal growth factor receptor (EGFR) pathway is able to drive oncogenesis in multiple human cancers, including head and neck squamous cell carcinoma. Targeted agents such as cetuximab and erlotinib are currently used in patients with head and neck squamous cell carcinoma, but, in this disease, the genomic alterations that cause pathway activation and determine response to pharmacologic inhibition remain ill-defined. Here, we present a detailed dissection of the EGFR/PI3K pathway, composed of sequencing of the core pathway components, and high-resolution genomic copy number assessment. Mutations were found in PIK3CA (6%), but no point mutations were observed in other pathway genes such as PTEN and EGFR . In contrast, we observed frequent copy number alterations of genes in the pathway, including PIK3CA , EGFR , protein tyrosine phosphatase receptor S ( PTPRS ), and RICTOR . In total, activating genetic pathway alterations were identified in 74% of head and neck tumors. Importantly, intragenic microdeletions of the EGFR phosphatase PTPRS were frequent (26%), identifying this gene as a target of 19p13 loss. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations. These findings have important implications for our understanding of head and neck cancer tumorigenesis and for the use of targeted agents for this malignancy.

Objective To define the incidence and risk factors of metastatic disease, and the effectiveness of salvage therapy, in esthesioneuroblastoma (ENB). Study Design Retrospective analysis of 57 patients presenting from 1979 through 2009. Methods Cumulative incidence of neck failure, distant failure and survival were assessed using the Kaplan-Meier method. Results Overall survival for all patients was 85% at 5 years and 75% at 10 years. Overall survival was negatively impacted by intracranial tumor extension (p<0.001), positive resection margins (p=0.05), and neck metastases (p=0.017). Neck lymph nodes were not electively irradiated during this time period. Nodal metastases developed in 17% of patients at a median time of 60 months. Kadish stage was not associated with risk of nodal metastasis (p=0.78). After treatment for nodal recurrence, locoregional control was achieved in 78% of patients. Of patients developing nodal recurrence, more than half developed distant metastases. The cumulative incidence of distant metastasis was 39% at a median time of 40 months. Patients who presented with Kadish stage C or D had a significantly increased risk of distant failure (p<0.001). In patients developing nodal (p=0.017) or distant metastasis (p=0.001) the probability of survival was significantly decreased. Conclusion Regional and distant metastases in patients with esthesioneuroblastoma occur in a delayed fashion and negatively impact survival. Neck nodal recurrence may be a harbinger of distant metastases. At MSKCC we now treat the majority of ENB patients with elective nodal irradiation. However, the chief obstacle to long-term cure is distant metastases.

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