{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T21:05:09Z","timestamp":1789419909134,"version":"build-2803163510"},"reference-count":137,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute (NCI)","award":["R01CA258692"],"award-info":[{"award-number":["R01CA258692"]}]},{"name":"National Cancer Institute (NCI)","award":["R01CA249087"],"award-info":[{"award-number":["R01CA249087"]}]},{"name":"National Institutes of Health (NIH)","award":["R01CA258692"],"award-info":[{"award-number":["R01CA258692"]}]},{"name":"National Institutes of Health (NIH)","award":["R01CA249087"],"award-info":[{"award-number":["R01CA249087"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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 \u201cappendix cancer\u201d, \u201cappendiceal cancer\u201d, \u201cpseudomyxoma peritonei\u201d, \u201csequencing\u201d, \u201cmutation\u201d, and \u201cgenotype\u201d. Results: AC comprises five major histologic subtypes\u2014appendiceal neuroendocrine neoplasms (ANENs), mucinous appendiceal neoplasms (MANs), goblet cell adenocarcinomas (GCAs), colonic-type adenocarcinomas (CTAs) and signet ring cell adenocarcinomas (SRCs)\u2014each 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.<\/jats:p>","DOI":"10.3390\/cancers17193275","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:54:31Z","timestamp":1760028871000},"page":"3275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Genomic Topography of Appendiceal Cancers: Our Current Understanding, Clinical Perspectives, and Future Directions"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0362-4890","authenticated-orcid":false,"given":"Daniel J.","family":"Gironda","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Wake Forest Organoid Research Center, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4649-0450","authenticated-orcid":false,"given":"Richard A.","family":"Erali","sequence":"additional","affiliation":[{"name":"Wake Forest Organoid Research Center, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Department of Surgery, Section of Surgical Oncology, Atrium Health Wake Forest Baptist, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4099-6642","authenticated-orcid":false,"given":"Steven D.","family":"Forsythe","sequence":"additional","affiliation":[{"name":"Wake Forest Organoid Research Center, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Neuroendocrine Cancer Therapy Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-3310","authenticated-orcid":false,"given":"Ashok K.","family":"Pullikuth","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Wake Forest Organoid Research Center, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4681-8054","authenticated-orcid":false,"given":"Rui","family":"Zheng-Pywell","sequence":"additional","affiliation":[{"name":"Department of Surgery, Section of Surgical Oncology, Atrium Health Wake Forest Baptist, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"Cummins","sequence":"additional","affiliation":[{"name":"Department of Surgery, Section of Surgical Oncology, Atrium Health Wake Forest Baptist, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shay","family":"Soker","sequence":"additional","affiliation":[{"name":"Wake Forest Organoid Research Center, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyong","family":"Gui","sequence":"additional","affiliation":[{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA"},{"name":"Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7683-9502","authenticated-orcid":false,"given":"Edward A.","family":"Levine","sequence":"additional","affiliation":[{"name":"Wake Forest Organoid Research Center, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Department of Surgery, Section of Surgical Oncology, Atrium Health Wake Forest Baptist, Winston-Salem, NC 27157, USA"},{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos I.","family":"Votanopoulos","sequence":"additional","affiliation":[{"name":"Wake Forest Organoid Research Center, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Department of Surgery, Section of Surgical Oncology, Atrium Health Wake Forest Baptist, Winston-Salem, NC 27157, USA"},{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3799-2528","authenticated-orcid":false,"given":"Lance D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Wake Forest Organoid Research Center, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1002\/1097-0142(19950201)75:3<757::AID-CNCR2820750303>3.0.CO;2-F","article-title":"Epithelial Noncarcinoid Tumors and Tumor-Like Lesions of the Appendix: A Clinicopathologic Study of 184 Patients with a Multivariate Analysis of Prognostic Factors","volume":"75","author":"Carr","year":"1995","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1038\/s41379-022-01114-7","article-title":"Clinicopathologic parameters and outcomes of mucinous neoplasms confined to the appendix: A benign entity with excellent prognosis","volume":"35","author":"Polydorides","year":"2022","journal-title":"Mod. 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