The Genomic Topography of Appendiceal Cancers: Our Current Understanding, Clinical Perspectives, and Future Directions

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Background/Objectives: Appendiceal cancer (AC) is a rare and understudied malignancy with limited genomic data available to guide clinical interventions. Historically treated as a subtype of colorectal cancer, AC is now recognized as a distinct disease with unique histologic subtypes and molecular features. This review aims to consolidate current genomic data across AC subtypes and explore the clinical relevance of recurrent mutations. Methods: A systematic literature review was performed in accordance with general Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines. Using search engines such as PubMed and Web of Science, we selected studies based on relevance to AC genomics using search terms such as “appendix cancer”, “appendiceal cancer”, “pseudomyxoma peritonei”, “sequencing”, “mutation”, and “genotype”. Results: AC comprises five major histologic subtypes—appendiceal neuroendocrine neoplasms (ANENs), mucinous appendiceal neoplasms (MANs), goblet cell adenocarcinomas (GCAs), colonic-type adenocarcinomas (CTAs) and signet ring cell adenocarcinomas (SRCs)—each with unique clinical behaviors and mutational profiles. Low-grade tumors, such as ANENs and MANs, frequently harbor KRAS and GNAS mutations, while high-grade subtypes, such as CTAs and SRCs, are enriched for TP53, APC, and SMAD gene alterations. GCA tumors exhibit a distinct mutational spectrum involving chromatin remodeling genes such as ARID1A and KMT2D. Compared to colorectal cancer, AC demonstrates lower frequencies of APC and TP53 mutations and a higher prevalence of GNAS mutations, consistent with a pathological divergence from CRC. Conclusions: The genomic heterogeneity of AC is commensurate with its histological complexity and has important implications for diagnosis, prognosis and treatment. While certain actionable mutations are present in a subset of tumors, large-scale genomic characterization efforts and development of subtype-specific models will be essential for advancing precision medicine in AC.

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