Shamir ER, et al. - To better describe the molecular pathogenesis of colorectal neuroendocrine carcinoma, researchers used capture-based next-generation sequencing on 25 cases and evaluating the expression of p53, Rb, p16, and high-risk human papillomavirus (HR-HPV) subtypes using immunohistochemistry, in situ hybridization, and polymerase chain reaction. Like neuroendocrine carcinomas in other anatomic sites, this data establishes how vital Rb/E2F pathway dysregulation is in the pathogenesis of colorectal neuroendocrine carcinoma. Furthermore, three distinct molecular subgroups of colorectal neuroendocrine carcinomas were identified, which can be distinguished based on Rb protein and HR-HPV status. In cases without genomic alterations in either gene, HR-HPV infection is a distinct mechanism for Rb and p53 inactivation. Improvement in patient outcomes could be achieved via differential treatment strategies for hypermutated and HPV-driven cases.