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

被引：402

作者：

Bonilla, Ximena ^{[1
]}

Parmentier, Laurent ^{[2
]}

King, Bryan ^{[3
]}

Bezrukov, Fedor ^{[4
,5
]}

Kaya, Gurkan ^{[6
]}

Zoete, Vincent ^{[7
]}

Seplyarskiy, Vladimir B. ^{[8
,9
,10
]}

Sharpe, Hayley J. ^{[11
]}

McKee, Thomas ^{[12
]}

Letourneau, Audrey ^{[1
]}

Ribaux, Pascale G. ^{[1
]}

Popadin, Konstantin ^{[1
]}

Basset-Seguin, Nicole ^{[13
]}

Ben Chaabene, Rouaa ^{[1
]}

Santoni, Federico A. ^{[1
,14
]}

Andrianova, Maria A. ^{[8
,9
,10
]}

Guipponi, Michel ^{[14
]}

Garieri, Marco ^{[1
]}

Verdan, Carole ^{[12
]}

Grosdemange, Kerstin ^{[6
]}

Sumara, Olga ^{[15
]}

Eilers, Martin ^{[15
,16
]}

Aifantis, Iannis ^{[3
]}

Michielin, Olivier ^{[7
,17
,18
]}

de Sauvage, Frederic J. ^{[11
]}

Antonarakis, Stylianos E. ^{[1
,14
,19
]}

Nikolaev, Sergey I. ^{[1
,14
]}

机构：

[1] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[2] Hosp Valais, Dept Dermatol, Sierre, Switzerland

[3] NYU, Sch Med, Dept Pathol, New York, NY USA

[4] Univ Connecticut, Dept Phys, Storrs, CT USA

[5] Brookhaven Natl Lab, RIKEN BNL Res Ctr, Upton, NY 11973 USA

[6] Univ Hosp Geneva, Dept Dermatol, Geneva, Switzerland

[7] Swiss Inst Bioinformat, Lausanne, Switzerland

[8] Russian Acad Sci, Inst Informat Transmiss Problems, Moscow, Russia

[9] Pirogov Russian Natl Res Med Univ, Moscow, Russia

[10] Moscow MV Lomonosov State Univ, Moscow, Russia

[11] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA

[12] Univ Hosp Geneva, Serv Clin Pathol, Geneva, Switzerland

[13] Univ Paris 07, St Louis Hosp, Dept Dermatol, Paris, France

[14] Univ Hosp Geneva, Serv Genet Med, Geneva, Switzerland

[15] Univ Wurzburg, Dept Biochem & Mol Biol, D-97070 Wurzburg, Germany

[16] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, D-97070 Wurzburg, Germany

[17] Univ Lausanne, Dept Oncol, Lausanne, Switzerland

[18] CHU Vaudois, CH-1011 Lausanne, Switzerland

[19] Inst Genet & Genom Geneva iGE3, Geneva, Switzerland

来源：

NATURE GENETICS | 2016年 / 48卷 / 04期

关键词：

HEDGEHOG SIGNALING PATHWAY; KINETOCHORE GENE KNSTRN; C-MYC; TUMOR-SUPPRESSOR; MUTATIONAL LANDSCAPE; UBIQUITIN LIGASE; POINT MUTATIONS; CANCER; GROWTH; TRANSCRIPTION;

D O I：

10.1038/ng.3525

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 x 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.

引用

页码：398 / +

页数：11

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