{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:23:11Z","timestamp":1792174991126,"version":"4.4.0"},"reference-count":247,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T00:00:00Z","timestamp":1689120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Romanian Executive Agency for Higher Education, Research, Development, and Innovation","award":["FDI 0690\/2023"],"award-info":[{"award-number":["FDI 0690\/2023"]}]},{"name":"Romanian Executive Agency for Higher Education, Research, Development, and Innovation","award":["108630"],"award-info":[{"award-number":["108630"]}]},{"name":"European Regional Development Fund through the Competitiveness Operational Program 2014\u20132020","award":["FDI 0690\/2023"],"award-info":[{"award-number":["FDI 0690\/2023"]}]},{"name":"European Regional Development Fund through the Competitiveness Operational Program 2014\u20132020","award":["108630"],"award-info":[{"award-number":["108630"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>In appendiceal cancers, the most frequently mutated genes are (i) KRAS, which, when reactivated, restores signal transduction via the RAS\u2013RAF\u2013MEK\u2013ERK 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\u2013RAF\u2013MEK\u2013ERK 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\u2013RAF\u2013MEK\u2013ERK 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.<\/jats:p>","DOI":"10.3390\/cancers15143591","type":"journal-article","created":{"date-parts":[[2023,7,13]],"date-time":"2023-07-13T02:14:48Z","timestamp":1689214488000},"page":"3591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Landscape of Genetic Mutations in Appendiceal Cancers"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8270-7031","authenticated-orcid":false,"given":"Marian","family":"Constantin","sequence":"first","affiliation":[{"name":"Institute of Biology of Romanian Academy, 060031 Bucharest, Romania"},{"name":"The Research Institute of the University of Bucharest (ICUB), 050095 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"M\u0103tanie","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Animal Physiology and Biophysics (DAFAB), Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9264-1603","authenticated-orcid":false,"given":"Livia","family":"Petrescu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Animal Physiology and Biophysics (DAFAB), Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Bolocan","sequence":"additional","affiliation":[{"name":"Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9053-0018","authenticated-orcid":false,"given":"Octavian","family":"Andronic","sequence":"additional","affiliation":[{"name":"Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9031-338X","authenticated-orcid":false,"given":"Coralia","family":"Bleotu","sequence":"additional","affiliation":[{"name":"Life, Environmental and Earth Sciences Division, The Research Institute of the University of Bucharest (ICUB), 050095 Bucharest, Romania"},{"name":"Stefan S. Nicolau Institute of Virology, 030304 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela Magdalena","family":"Mitache","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cTitu Maiorescu\u201d University, 040441 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sorin","family":"Tudorache","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cTitu Maiorescu\u201d University, 040441 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2409-0966","authenticated-orcid":false,"given":"Corneliu Ovidiu","family":"Vrancianu","sequence":"additional","affiliation":[{"name":"The Research Institute of the University of Bucharest (ICUB), 050095 Bucharest, Romania"},{"name":"Microbiology\u2014Immunology Department, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania"},{"name":"National Institute of Research and Development for Biological Sciences, 060031 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s10140-014-1206-4","article-title":"Anatomical variants and pathologies of the vermix","volume":"21","author":"Deshmukh","year":"2014","journal-title":"Emerg. 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Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=KMT2D."},{"key":"ref_172","unstructured":"(2022, October 18). RAD51C Gene\u2014RAD51 Paralog C. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=RAD51C."},{"key":"ref_173","unstructured":"(2022, October 18). SETD2 Gene\u2014SET Domain Containing 2, Histone Lysine Methyltransferase. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=SETD2."},{"key":"ref_174","unstructured":"(2022, August 30). TRPS1 Gene\u2014Transcriptional Repressor GATA Binding 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=TRPS1."},{"key":"ref_175","unstructured":"(2022, October 17). CDH1 Gene\u2014Cadherin 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=CDH1."},{"key":"ref_176","unstructured":"(2022, October 17). CSMD1 Gene\u2014CUB and Sushi Multiple Domains 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=CSMD1."},{"key":"ref_177","unstructured":"(2022, October 17). CTNNA1 Gene\u2014Catenin Alpha 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=CTNNA1."},{"key":"ref_178","unstructured":"(2022, October 17). CTNNB1 Gene\u2014Catenin Beta 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=CTNNB1."},{"key":"ref_179","unstructured":"(2022, October 17). CNTNAP2 Gene\u2014Contactin Associated Protein 2. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=CNTNAP2."},{"key":"ref_180","unstructured":"(2022, October 18). LAMA1 Gene\u2014Laminin Subunit Alpha 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=LAMA1."},{"key":"ref_181","unstructured":"(2022, October 18). SPTA1 Gene\u2014Spectrin Alpha, Erythrocytic 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=SPTA1."},{"key":"ref_182","unstructured":"(2022, October 17). ALK Gene\u2014ALK Receptor Tyrosine Kinase. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=ALK."},{"key":"ref_183","unstructured":"(2022, October 17). ARID1A Gene\u2014AT-Rich Interaction Domain 1A. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=ARID1A."},{"key":"ref_184","unstructured":"(2022, October 17). ARID2 Gene\u2014AT-Rich Interaction Domain 2. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=ARID2."},{"key":"ref_185","unstructured":"(2022, October 17). ATM Gene\u2014ATM Serine\/Threonine Kinase. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=ATM."},{"key":"ref_186","unstructured":"(2022, October 17). CARD11 Gene\u2014Caspase Recruitment Domain Family Member 11. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=CARD11."},{"key":"ref_187","unstructured":"(2022, October 17). DCLK1 Gene\u2014Doublecortin Like Kinase 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=DCLK1."},{"key":"ref_188","unstructured":"(2022, October 17). DIS3 Gene\u2014DIS3 Homolog, Exosome Endoribonuclease and 3\u2032-5\u2032 Exoribonuclease. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=DIS3."},{"key":"ref_189","unstructured":"(2022, October 17). FH Gene\u2014Fumarate Hydratase. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=FH."},{"key":"ref_190","unstructured":"(2022, October 17). IDH2 Gene\u2014Isocitrate Dehydrogenase (NADP+) 2. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=IDH2."},{"key":"ref_191","unstructured":"(2022, October 18). PRKACA Gene\u2014Protein Kinase CAMP-Activated Catalytic Subunit Alpha. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=PRKACA."},{"key":"ref_192","unstructured":"(2022, October 18). PTPN11 Gene\u2014Protein Tyrosine Phosphatase Non-Receptor Type 11. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=PTPN11."},{"key":"ref_193","unstructured":"(2022, October 18). RHPN2 Gene\u2014Rhophilin Rho GTPase Binding Protein 2. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=RHPN2."},{"key":"ref_194","unstructured":"(2022, October 18). SMARCA4 Gene\u2014SWI\/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 4. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=SMARCA4."},{"key":"ref_195","unstructured":"(2022, August 30). TRRAP Gene\u2014Transformation\/Transcription Domain Associated Protein. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=TRRAP."},{"key":"ref_196","unstructured":"(2022, August 30). USP9X Gene\u2014Ubiquitin Specific Peptidase 9 X-Linked. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=USP9X."},{"key":"ref_197","unstructured":"(2022, October 17). ABCA7 Gene\u2014ATP Binding Cassette Subfamily A Member 7. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=ABCA7."},{"key":"ref_198","unstructured":"(2022, October 17). ANKRD24 Gene\u2014Ankyrin Repeat Domain 24. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=ANKRD24."},{"key":"ref_199","unstructured":"(2022, October 17). APOB Gene\u2014Apolipoprotein B. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=APOB."},{"key":"ref_200","unstructured":"(2022, October 17). ASXL1 Gene\u2014ASXL Transcriptional Regulator 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=ASXL1."},{"key":"ref_201","unstructured":"(2022, October 17). BCOR Gene\u2014BCL6 Corepressor. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=BCOR."},{"key":"ref_202","unstructured":"(2022, October 17). CRY2 Gene\u2014Cryptochrome Circadian Regulator 2. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=CRY2."},{"key":"ref_203","unstructured":"(2022, October 17). DOCK3\u2014Dedicator of Cytokinesis 3. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=DOCK3."},{"key":"ref_204","unstructured":"(2022, October 17). DOK6 Gene\u2014Docking Protein 6. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=DOK6."},{"key":"ref_205","unstructured":"(2022, October 17). EEF1A1 Gene\u2014Eukaryotic Translation Elongation Factor 1 Alpha 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=EEF1A1."},{"key":"ref_206","unstructured":"(2022, October 17). EPHA10 Gene\u2014EPH Receptor A10. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=EPHA10."},{"key":"ref_207","unstructured":"(2022, October 17). FAT1 Gene\u2014FAT Atypical Cadherin 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=FAT1."},{"key":"ref_208","unstructured":"(2022, October 17). FAT4 Gene\u2014FAT Atypical Cadherin 4. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=FAT4."},{"key":"ref_209","unstructured":"(2022, October 17). FBXW7 Gene\u2014F-Box and WD Repeat Domain Containing 7. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=FBXW7."},{"key":"ref_210","unstructured":"(2022, October 17). IRX6 Gene\u2014Iroquois Homeobox 6. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=IRX6."},{"key":"ref_211","unstructured":"(2022, October 18). KRT37 Gene\u2014Keratin 37. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=KRT37."},{"key":"ref_212","unstructured":"(2022, October 18). MED12 Gene\u2014Mediator Complex Subunit 12. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=MED12."},{"key":"ref_213","unstructured":"(2022, October 18). MTIF2 Gene\u2014Mitochondrial Translational Initiation Factor 2. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=MTIF2."},{"key":"ref_214","unstructured":"(2022, October 18). MUC16 Gene\u2014Mucin 16, Cell Surface Associated. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=MUC16."},{"key":"ref_215","doi-asserted-by":"crossref","unstructured":"Shibahara, H., Higashi, M., Yokoyama, S., Rousseau, K., Kitazono, I., Osako, M., Shirahama, H., Tashiro, Y., Kurumiya, Y., and Narita, M. (2014). A comprehensive expression analysis of mucins in appendiceal carcinoma in a multicenter study: MUC3 is a novel prognostic factor. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115613"},{"key":"ref_216","unstructured":"(2022, October 18). OCA2 Gene\u2014OCA2 Melanosomal Transmembrane Protein. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=OCA2."},{"key":"ref_217","unstructured":"(2022, October 18). PCDH10 Gene\u2014Protocadherin 10. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=PCDH10."},{"key":"ref_218","unstructured":"(2022, October 18). PCDH17 Gene\u2014Protocadherin 17. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=PCDH17."},{"key":"ref_219","unstructured":"(2022, October 18). POM121L12 Gene\u2014POM121 Transmembrane Nucleoporin Like 12. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=POM121L12."},{"key":"ref_220","unstructured":"(2022, October 18). PRDM1 Gene\u2014PR\/SET Domain 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=PRDM1."},{"key":"ref_221","unstructured":"(2022, October 18). PTCHD3 Gene\u2014Patched Domain Containing 3 (Gene\/Pseudogene). Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=PTCHD3."},{"key":"ref_222","unstructured":"(2022, October 18). RNF43 Gene\u2014Ring Finger Protein 43. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=RNF43."},{"key":"ref_223","unstructured":"(2022, October 18). SNTG1 Gene\u2014Syntrophin Gamma 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=SNTG1."},{"key":"ref_224","unstructured":"(2022, October 18). SOX9 Gene\u2014SRY-Box Transcription Factor 9. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=2022."},{"key":"ref_225","unstructured":"(2022, August 30). STK11 Gene\u2014Serine\/Threonine Kinase 11. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=STK11."},{"key":"ref_226","unstructured":"(2022, August 30). TSC1 Gene\u2014TSC Complex Subunit 1. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=TSC12022."},{"key":"ref_227","unstructured":"(2022, August 30). TSC2 Gene\u2014TSC Complex Subunit 2. Available online: https:\/\/www.genecards.org\/cgi-bin\/carddisp.pl?gene=TSC2."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1111\/j.1743-7563.2010.01335.x","article-title":"Microsatellite instability in colorectal cancer","volume":"6","author":"Iacopetta","year":"2010","journal-title":"Asia Pac. J. Clin. Oncol."},{"key":"ref_229","doi-asserted-by":"crossref","unstructured":"Amato, M., Franco, R., Facchini, G., Addeo, R., Ciardiello, F., Berretta, M., Vita, G., Sgambato, A., Pignata, S., and Caraglia, M. (2022). Microsatellite Instability: From the Implementation of the Detection to a Prognostic and Predictive Role in Cancers. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158726"},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/978-1-4939-9773-2_5","article-title":"Detection of Microsatellite Instability Biomarkers via Next-Generation Sequencing","volume":"2055","author":"Bonneville","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12935-019-1091-8","article-title":"Microsatellite instability: A review of what the oncologist should know","volume":"20","author":"Li","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1038\/s41436-020-0892-4","article-title":"Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: Findings from the Prospective Lynch Syndrome Database","volume":"22","author":"Sampson","year":"2020","journal-title":"Genet. Med."},{"key":"ref_233","doi-asserted-by":"crossref","unstructured":"Bucksch, K., Zachariae, S., Aretz, S., B\u00fcttner, R., Holinski-Feder, E., Holzapfel, S., H\u00fcneburg, R., Kloor, M., von Knebel Doeberitz, M., and Morak, M. (2020). Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: A prospective cohort study. BMC Cancer., 20.","DOI":"10.1186\/s12885-020-06926-x"},{"key":"ref_234","first-page":"694","article-title":"Appendiceal carcinoma associated with microsatellite instability","volume":"8","author":"Rosado","year":"2018","journal-title":"Mol. Clin. Oncol."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1097\/PAS.0b013e318282649b","article-title":"High-level microsatellite instability in appendiceal carcinomas","volume":"37","author":"Taggart","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_236","doi-asserted-by":"crossref","unstructured":"Bonneville, R., Krook, M.A., Kautto, E.A., Miya, J., Wing, M.R., Chen, H.Z., Reeser, J.W., Yu, L., and Roychowdhury, S. (2017). Landscape of microsatellite instability across 39 cancer types. JCO Precis. 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