title: Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.
abstract: Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Ximena
authors.initials: X
authors.lastname: Bonilla
authors.affiliation: Department of Dermatology, Hospital of Valais, Sierre, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Parmentier
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: King
authors.affiliation: Department of Physics, University of Connecticut, Storrs, Connecticut, USA.|RIKEN BNL Research Center, Brookhaven National Laboratory, Upton, New York, USA.
authors.forename: Fedor
authors.identifier: http://orcid.org/0000-0003-3601-1003
authors.initials: F
authors.lastname: Bezrukov
authors.affiliation: Department of Dermatology, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Gürkan
authors.initials: G
authors.lastname: Kaya
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.affiliation: Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia.|Pirogov Russian National Research Medical University, Moscow, Russia.|Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Seplyarskiy
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Hayley J
authors.initials: HJ
authors.lastname: Sharpe
authors.affiliation: Service of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: McKee
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Letourneau
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Pascale G
authors.initials: PG
authors.lastname: Ribaux
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Popadin
authors.affiliation: Department of Dermatology, Saint Louis Hospital, Paris 7 University, Paris, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Basset-Seguin
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Rouaa
authors.initials: R
authors.lastname: Ben Chaabene
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.|Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Federico A
authors.initials: FA
authors.lastname: Santoni
authors.affiliation: Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia.|Pirogov Russian National Research Medical University, Moscow, Russia.|Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Andrianova
authors.affiliation: Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Garieri
authors.affiliation: Service of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Verdan
authors.affiliation: Department of Dermatology, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Grosdemange
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Sumara
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-0376-6533
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.|Department of Oncology, University of Lausanne and Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.|Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.|Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.|Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Nikolaev
mesh_terms: D000813:Anilides / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D063646:Carcinogenesis / Q000235:genetics; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D059472:Exome; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D011725:Pyridines / Q000627:therapeutic use; D015398:Signal Transduction / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C538724:HhAntag691; D011725:Pyridines