title: Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors.
abstract: 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 FGFR3, PIK3CA, KRAS, HRAS, EGFR, and AKT1 oncogenes but not in tumor suppressor genes TSC1 and PTEN. 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.
authors.affiliation: Department of Dermatology, University of Regensburg, 93042 Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hafner
authors.forename: Agustí
authors.initials: A
authors.lastname: Toll
authors.forename: Alejandro
authors.initials: A
authors.lastname: Fernández-Casado
authors.forename: Julie
authors.initials: J
authors.lastname: Earl
authors.forename: Miriam
authors.initials: M
authors.lastname: Marqués
authors.forename: Francesco
authors.initials: F
authors.lastname: Acquadro
authors.forename: Marinela
authors.initials: M
authors.lastname: Méndez-Pertuz
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
authors.forename: Julie E
authors.initials: JE
authors.lastname: Burns
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Knowles
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cigudosa
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.forename: Michael
authors.initials: M
authors.lastname: Landthaler
authors.forename: Ramón M
authors.initials: RM
authors.lastname: Pujol
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D002999:Clone Cells; D004252:DNA Mutational Analysis; D005820:Genetic Testing; D015894:Genome, Human / Q000235:genetics; D005838:Genotype; D006801:Humans; D017492:Keratosis, Seborrheic / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051498:Receptor, Fibroblast Growth Factor, Type 3; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C000624650:TSC1 protein, human; C496365:FGFR3 protein, human; C494929:PTEN protein, human