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

Ximena Bonilla; Laurent Parmentier; Bryan King; Fedor Bezrukov; Gürkan Kaya; Vincent Zoete; Vladimir B. Seplyarskiy; Hayley J. Sharpe; Thomas McKee; Audrey Letourneau; Pascale G. Ribaux; Konstantin Popadin; Nicole Basset-Seguin; Rouaa Ben Chaabene; Federico A. Santoni; Maria A. Andrianova; Michel Guipponi; Marco Garieri; Carole Verdan; Kerstin Grosdemange; Olga Sumara; Martin Eilers; Iannis Aifantis; Olivier Michielin; Frederic J. De Sauvage; Stylianos E. Antonarakis; Sergey I. Nikolaev

doi:10.1038/ng.3525

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

Ximena Bonilla, Laurent Parmentier, Bryan King, Fedor Bezrukov, Gürkan Kaya, Vincent Zoete, Vladimir B. Seplyarskiy, Hayley J. Sharpe, Thomas McKee, Audrey Letourneau, Pascale G. Ribaux, Konstantin Popadin, Nicole Basset-Seguin, Rouaa Ben Chaabene, Federico A. Santoni, Maria A. Andrianova, Michel Guipponi, Marco Garieri, Carole Verdan, Kerstin GrosdemangeOlga Sumara, Martin Eilers, Iannis Aifantis, Olivier Michielin, Frederic J. De Sauvage, Stylianos E. Antonarakis, Sergey I. Nikolaev^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	398-406
Number of pages	9
Journal	Nature Genetics
Volume	48
Issue number	4
DOIs	https://doi.org/10.1038/ng.3525
Publication status	Published - 29 Mar 2016

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Bonilla, X., Parmentier, L., King, B., Bezrukov, F., Kaya, G., Zoete, V., Seplyarskiy, V. B., Sharpe, H. J., McKee, T., Letourneau, A., Ribaux, P. G., Popadin, K., Basset-Seguin, N., Chaabene, R. B., Santoni, F. A., Andrianova, M. A., Guipponi, M., Garieri, M., Verdan, C., ... Nikolaev, S. I. (2016). Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nature Genetics, 48(4), 398-406. https://doi.org/10.1038/ng.3525

@article{aad40b3840164f7d9f4c0894e3c6b209,

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.",

author = "Ximena Bonilla and Laurent Parmentier and Bryan King and Fedor Bezrukov and G{\"u}rkan Kaya and Vincent Zoete and Seplyarskiy, {Vladimir B.} and Sharpe, {Hayley J.} and Thomas McKee and Audrey Letourneau and Ribaux, {Pascale G.} and Konstantin Popadin and Nicole Basset-Seguin and Chaabene, {Rouaa Ben} and Santoni, {Federico A.} and Andrianova, {Maria A.} and Michel Guipponi and Marco Garieri and Carole Verdan and Kerstin Grosdemange and Olga Sumara and Martin Eilers and Iannis Aifantis and Olivier Michielin and {De Sauvage}, {Frederic J.} and Antonarakis, {Stylianos E.} and Nikolaev, {Sergey I.}",

year = "2016",

month = mar,

day = "29",

doi = "10.1038/ng.3525",

language = "English",

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Bonilla, X, Parmentier, L, King, B, Bezrukov, F, Kaya, G, Zoete, V, Seplyarskiy, VB, Sharpe, HJ, McKee, T, Letourneau, A, Ribaux, PG, Popadin, K, Basset-Seguin, N, Chaabene, RB, Santoni, FA, Andrianova, MA, Guipponi, M, Garieri, M, Verdan, C, Grosdemange, K, Sumara, O, Eilers, M, Aifantis, I, Michielin, O, De Sauvage, FJ, Antonarakis, SE & Nikolaev, SI 2016, 'Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma', Nature Genetics, vol. 48, no. 4, pp. 398-406. https://doi.org/10.1038/ng.3525

TY - JOUR

T1 - Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma

AU - Bonilla, Ximena

AU - Parmentier, Laurent

AU - King, Bryan

AU - Bezrukov, Fedor

AU - Kaya, Gürkan

AU - Zoete, Vincent

AU - Seplyarskiy, Vladimir B.

AU - Sharpe, Hayley J.

AU - McKee, Thomas

AU - Letourneau, Audrey

AU - Ribaux, Pascale G.

AU - Popadin, Konstantin

AU - Basset-Seguin, Nicole

AU - Chaabene, Rouaa Ben

AU - Santoni, Federico A.

AU - Andrianova, Maria A.

AU - Guipponi, Michel

AU - Garieri, Marco

AU - Verdan, Carole

AU - Grosdemange, Kerstin

AU - Sumara, Olga

AU - Eilers, Martin

AU - Aifantis, Iannis

AU - Michielin, Olivier

AU - De Sauvage, Frederic J.

AU - Antonarakis, Stylianos E.

AU - Nikolaev, Sergey I.

PY - 2016/3/29

Y1 - 2016/3/29

N2 - 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.

AB - 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.

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U2 - 10.1038/ng.3525

DO - 10.1038/ng.3525

M3 - Article

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AN - SCOPUS:84960145215

SN - 1061-4036

VL - 48

SP - 398

EP - 406

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

Abstract

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