Landscape of Genetic Mutations in Appendiceal Cancers

SIMPLE SUMMARY: An analysis of the presence of mutations of 105 genes in appendiceal cancers through the lens of the reviewed literature supports the view that in most of them, the inactivation of tumor suppressor genes, such as TP53 and SMAD4, is required in parallel with the reactivation of genes with oncogenic potentials, such as KRAS, GNAS, and BRAF, which support the main tumor processes, cell proliferation, angiogenesis, and evasion of apoptosis. Of all appendiceal cancers, the most mutated genes are reported in mucinous neoplasms of the appendix, not including those in the RAS–RAF–MEK–ERK signaling pathway, followed by low-grade appendiceal mucinous neoplasms, appendiceal goblet cell adenocarcinomas, and mucinous adenocarcinomas of the appendix, in which this signaling pathway is most frequently affected, showing its importance in their tumorigenesis. Microsatellite instability rarely occurs in appendix cancers, being reported only in adenocarcinomas. ABSTRACT: In appendiceal cancers, the most frequently mutated genes are (i) KRAS, which, when reactivated, restores signal transduction via the RAS–RAF–MEK–ERK signaling pathway and stimulates cell proliferation in the early stages of tumor transformation, and then angiogenesis; (ii) TP53, whose inactivation leads to the inhibition of programmed cell death; (iii) GNAS, which, when reactivated, links the cAMP pathway to the RAS–RAF–MEK–ERK signaling pathway, stimulating cell proliferation and angiogenesis; (iv) SMAD4, exhibiting typical tumor-suppressive activity, blocking the transmission of oncogenic TGFB signals via the SMAD2/SMAD3 heterodimer; and (v) BRAF, which is part of the RAS–RAF–MEK–ERK signaling pathway. Diverse mutations are reported in other genes, which are part of secondary or less critical signaling pathways for tumor progression, but which amplify the phenotypic diversity of appendiceal cancers. In this review, we will present the main genetic mutations involved in appendix tumors and their roles in cell proliferation and survival, and in tumor invasiveness, angiogenesis, and acquired resistance to anti-growth signals.