Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS , encoding the G-protein Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh-signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas mutants. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, illuminating G-protein modulation as a potential therapeutic avenue.
New tests have reduced an already low risk of TTI in Canada. HCV RR estimates by two different methods differed but both were low.
Dietary patterns reflect combinations of dietary exposures, and here we examine these in relation to prostate cancer risk. In a case-control study, 80 incident primary prostate cancer cases and 334 urology clinic controls were enrolled from 1997 through 1999 in Kingston, Ontario, Canada. Food-frequency questionnaires were completed prior to diagnosis and assessed intake in the 1-year period 2-3 years prior to enrollment. Among controls, dietary intake was used in principal components analyses to identify patterns that were then evaluated with all subjects in relation to prostate cancer risk using unconditional logistic regression, controlling for age. Prostate cancer is one of the most common cancer types in developed countries, with an estimated 20,100 new cases in 2004 in Canada. 1 Higher incidence rates occur in North America, Great Britain, Western Europe and Australia than in Asia, Latin America and Africa. 2 While genetic susceptibility is an established risk factor for prostate cancer, 2-5 the wide international variation in incidence points primarily to an environmental etiology. 6,7 The role of diet has been investigated in several epidemiologic studies, including dietary fat intake, vitamin A, carotenoids, fruits, vegetables, dairy products and soy products. 2,3,[7][8][9][10][11][12][13][14][15][16] The most consistent dietary component associated with prostate cancer risk is fat intake, 2 an association that is apparent despite differences in the quality of the study methods and assessment of dietary intake. [2][3][4]7,8,16 Recent attention has turned to a group of phytochemicals, particularly the isoflavones found in soybeans, 10,15 since Asians, with lower prostate cancer rates, have high consumption of soy products. Hypotheses regarding exposure to cadmium from foods such as shellfish and the risk of prostate cancer have not been substantiated by epidemiologic investigations. 2 Epidemiologic evidence supports an association between dietary factors and the risk of prostate cancer, but there are few consistent findings at a specific level. This is due in part to differences in measures of dietary intake, lack of variability in nutrient intakes among the population being studied and lack of control in the analysis for several possible confounders, including energy intake and lifestyle factors such as physical activity and smoking. 2,17,18 Further, potential associations between diet and prostate cancer risk may be concealed or lost when individual food items or nutrients are analyzed for their association with risk, as opposed to looking at groupings of habitually consumed foods. The metabolic and physiologic effects of combinations of foods on total risk are also unaccounted for when the conventional method of nutrient or individual food item analysis is used. 19 A broader consideration of patterns of food use may provide a more comprehensive assessment of the role of dietary factors on prostate cancer risk, given that foods are generally eaten in combination and together may have a greater impact on...
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