SummaryWe show that BRAFV600E initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic BrafV600E expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.

The decrease of acetylcholine receptors at neuromuscular junctions of myasthenic patients has been attributed to an antibody-mediated autoimmune process that accelerates receptor degradation. We studied the mechanism of this process in skeletal-muscle cultures, using intact antibodies and antibody fragments. Addition of myasthenic IgG or its divalent fragment, F(ab')2, to cultures accelerated the rate of acetylcholine-receptor degradation threefold. By contrast, the monovalent fragment, Fab, from myasthenic serum had no effect on degradation, although it bound to acetylcholine receptors. Addition of a second, "piggyback" antibody to cross-link the Fab:receptor complexes resulted in a threefold increase of the degradation rate. Similarly, when acetylcholine receptors with bound alpha-bungarotoxin were cross-linked by the addition of specific antibody against alpha-bungarotoxin, the degradation rate increased approximately threefold. The effect of myasthenic patients' antibodies in accelerating degradation of acetylcholine receptors is attributed to their ability to cross-link the receptors.

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KCNJ5 mutations are common in APA, particularly those arising from ZF. The long-recognized heterogeneity among APA may have a genetic basis.