This could be explained at least in part because most of the carcinogens, for which the mechanism of action is known, induce the activation of oncogenes such as K-ras [40,41,42], while the combinations of Trp53 and Rb alterations, responsible for the development of high-grade neuroendocrine tumors, are almost never found. Here, RB1 is linked to neuroendocrine neoplasm.