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Nat Genet. 2016 Apr;48(4):398-406. doi: 10.1038/ng.3525. Epub 2016 Mar 7.

Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.

Author information

1
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
2
Department of Dermatology, Hospital of Valais, Sierre, Switzerland.
3
Department of Pathology, New York University School of Medicine, New York, New York, USA.
4
Department of Physics, University of Connecticut, Storrs, Connecticut, USA.
5
RIKEN BNL Research Center, Brookhaven National Laboratory, Upton, New York, USA.
6
Department of Dermatology, University Hospitals of Geneva, Geneva, Switzerland.
7
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
8
Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia.
9
Pirogov Russian National Research Medical University, Moscow, Russia.
10
Lomonosov Moscow State University, Moscow, Russia.
11
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California, USA.
12
Service of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland.
13
Department of Dermatology, Saint Louis Hospital, Paris 7 University, Paris, France.
14
Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
15
Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany.
16
Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
17
Department of Oncology, University of Lausanne and Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
18
Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland.

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.

PMID:
26950094
DOI:
10.1038/ng.3525
[Indexed for MEDLINE]

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