{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:11:06Z","timestamp":1791231066208,"version":"4.1.0"},"reference-count":59,"publisher":"National Academy of Sciences","issue":"48","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,11,30]]},"abstract":"<jats:p>\n                    Malignant tumors result from the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Much less is known about the genetic changes in benign tumors. Seborrheic keratoses (SK) are very frequent benign human epidermal tumors without malignant potential. We performed a comprehensive mutational screen of genes in the FGFR3-RAS-MAPK and phosphoinositide 3-kinase (PI3K)-AKT pathways from 175 SK, including multiple lesions from each patient. SK commonly harbored multiple bona fide oncogenic mutations in\n                    <jats:italic>FGFR3<\/jats:italic>\n                    ,\n                    <jats:italic>PIK3CA, KRAS<\/jats:italic>\n                    ,\n                    <jats:italic>HRAS<\/jats:italic>\n                    ,\n                    <jats:italic>EGFR<\/jats:italic>\n                    , and\n                    <jats:italic>AKT1<\/jats:italic>\n                    oncogenes but not in tumor suppressor genes\n                    <jats:italic>TSC1<\/jats:italic>\n                    and\n                    <jats:italic>PTEN<\/jats:italic>\n                    . Despite the occurrence of oncogenic mutations and the evidence for downstream ERK\/MAPK and PI3K pathway signaling, we did not find induction of senescence or a DNA damage response. Array comparative genomic hybridization (aCGH) analysis revealed that SK are genetically stable. The pattern of oncogenic mutations and X chromosome inactivation departs significantly from randomness and indicates that spatially independent lesions from a given patient share a clonal relationship. Our findings show that multiple oncogenic mutations in the major signaling pathways involved in cancer are not sufficient to drive malignant tumor progression. Furthermore, our data provide clues on the origin and spread of oncogenic mutations in tissues, suggesting that apparently independent (multicentric) adult benign tumors may have a clonal origin.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1008365107","type":"journal-article","created":{"date-parts":[[2010,11,15]],"date-time":"2010-11-15T23:15:12Z","timestamp":1289862912000},"page":"20780-20785","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":86,"title":["Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors"],"prefix":"10.1073","volume":"107","author":[{"given":"Christian","family":"Hafner","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of Regensburg, 93042 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agust\u00ed","family":"Toll","sequence":"additional","affiliation":[{"name":"Servei de Dermatologia, Hospital del Mar-Institut Municipal d'Investigaci\u00f3 M\u00e8dica, Universitat Aut\u00f2noma de Barcelona, 08003 Barcelona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Fern\u00e1ndez-Casado","sequence":"additional","affiliation":[{"name":"Servei de Dermatologia, Hospital del Mar-Institut Municipal d'Investigaci\u00f3 M\u00e8dica, Universitat Aut\u00f2noma de Barcelona, 08003 Barcelona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Earl","sequence":"additional","affiliation":[{"name":"Grupo de Carcinog\u00e9nesis Epitelial, Programa de Patolog\u00eda Molecular, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Marqu\u00e9s","sequence":"additional","affiliation":[{"name":"Grupo de Carcinog\u00e9nesis Epitelial, Programa de Patolog\u00eda Molecular, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Acquadro","sequence":"additional","affiliation":[{"name":"Grupo de Citogen\u00e9tica Molecular and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, Programa de Gen\u00e9tica del C\u00e1ncer, Centro Nacional de Investigaciones Oncol\u00f3gicas, 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinela","family":"M\u00e9ndez-Pertuz","sequence":"additional","affiliation":[{"name":"Grupo de Carcinog\u00e9nesis Epitelial, Programa de Patolog\u00eda Molecular, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Urioste","sequence":"additional","affiliation":[{"name":"Grupo de Gen\u00e9tica Humana and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, Programa de Gen\u00e9tica del C\u00e1ncer Humano, Centro Nacional de Investigaciones Oncol\u00f3gicas, 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00faria","family":"Malats","sequence":"additional","affiliation":[{"name":"Grupo de Epidemiolog\u00eda Gen\u00e9tica y Molecular, Programa de Gen\u00e9tica del C\u00e1ncer, Centro Nacional de Investigaciones Oncol\u00f3gicas, 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie E.","family":"Burns","sequence":"additional","affiliation":[{"name":"Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Knowles","sequence":"additional","affiliation":[{"name":"Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Cigudosa","sequence":"additional","affiliation":[{"name":"Grupo de Citogen\u00e9tica Molecular and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, Programa de Gen\u00e9tica del C\u00e1ncer, Centro Nacional de Investigaciones Oncol\u00f3gicas, 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arndt","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Erlangen, 91054 Erlangen, Germany; 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