NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

Andrew P. South; Karin J. Purdie; Stephen A. Watt; Sam Haldenby; Nicoline den Breems; Michelle Dimon; Sarah T. Arron; Michael J. Kluk; Jon C. Aster; Angela McHugh; Dylan J. Xue; Jasbani H. S. Dayal; Kim S. Robinson; S. M. Hasan Rizvi; Charlotte M. Proby; Catherine A. Harwood; Irene M. Leigh

doi:10.1038/jid.2014.154

NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

Andrew P. South (Lead / Corresponding author), Karin J. Purdie, Stephen A. Watt, Sam Haldenby, Nicoline den Breems, Michelle Dimon, Sarah T. Arron, Michael J. Kluk, Jon C. Aster, Angela McHugh, Dylan J. Xue, Jasbani H. S. Dayal, Kim S. Robinson, S. M. Hasan Rizvi, Charlotte M. Proby, Catherine A. Harwood, Irene M. Leigh

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Abstract

Cutaneous SCC (cSCC) is the most frequent skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here we use massively parallel exome and targeted level sequencing 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.Journal of Investigative Dermatology accepted article preview online, 24 March 2014; doi:10.1038/jid.2014.154.

Original language	English
Pages (from-to)	2630-2638
Number of pages	9
Journal	Journal of Investigative Dermatology
Volume	134
Issue number	10
Early online date	17 Apr 2014
DOIs	https://doi.org/10.1038/jid.2014.154
Publication status	Published - Oct 2014

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10.1038/jid.2014.154

Dermatology and Genetic Medicine (Strategic Grant) (Joint with Kings College London)
Barton, G. (Investigator), Campbell, P. (Investigator), Hickerson, R. (Investigator), Leigh, I. (Investigator), McLean, I. (Investigator) & Wyatt, P. (Investigator)
1/08/12 → 30/04/19
Project: Research

Proby, Charlotte
- Cancer Research - Professor (Research Only) of Dermatology
Person: Academic

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South, A. P., Purdie, K. J., Watt, S. A., Haldenby, S., den Breems, N., Dimon, M., Arron, S. T., Kluk, M. J., Aster, J. C., McHugh, A., Xue, D. J., Dayal, J. H. S., Robinson, K. S., Rizvi, S. M. H., Proby, C. M., Harwood, C. A., & Leigh, I. M. (2014). NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis. Journal of Investigative Dermatology, 134(10), 2630-2638. https://doi.org/10.1038/jid.2014.154

@article{abb3723fafc944a1a401fc2cf732a25c,

title = "NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis",

abstract = "Cutaneous SCC (cSCC) is the most frequent skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here we use massively parallel exome and targeted level sequencing 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.Journal of Investigative Dermatology accepted article preview online, 24 March 2014; doi:10.1038/jid.2014.154.",

author = "South, {Andrew P.} and Purdie, {Karin J.} and Watt, {Stephen A.} and Sam Haldenby and {den Breems}, Nicoline and Michelle Dimon and Arron, {Sarah T.} and Kluk, {Michael J.} and Aster, {Jon C.} and Angela McHugh and Xue, {Dylan J.} and Dayal, {Jasbani H. S.} and Robinson, {Kim S.} and Rizvi, {S. M. Hasan} and Proby, {Charlotte M.} and Harwood, {Catherine A.} and Leigh, {Irene M.}",

year = "2014",

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doi = "10.1038/jid.2014.154",

language = "English",

volume = "134",

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South, AP, Purdie, KJ, Watt, SA, Haldenby, S, den Breems, N, Dimon, M, Arron, ST, Kluk, MJ, Aster, JC, McHugh, A, Xue, DJ, Dayal, JHS, Robinson, KS, Rizvi, SMH, Proby, CM, Harwood, CA & Leigh, IM 2014, 'NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis', Journal of Investigative Dermatology, vol. 134, no. 10, pp. 2630-2638. https://doi.org/10.1038/jid.2014.154

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T1 - NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

AU - South, Andrew P.

AU - Purdie, Karin J.

AU - Watt, Stephen A.

AU - Haldenby, Sam

AU - den Breems, Nicoline

AU - Dimon, Michelle

AU - Arron, Sarah T.

AU - Kluk, Michael J.

AU - Aster, Jon C.

AU - McHugh, Angela

AU - Xue, Dylan J.

AU - Dayal, Jasbani H. S.

AU - Robinson, Kim S.

AU - Rizvi, S. M. Hasan

AU - Proby, Charlotte M.

AU - Harwood, Catherine A.

AU - Leigh, Irene M.

PY - 2014/10

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N2 - Cutaneous SCC (cSCC) is the most frequent skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here we use massively parallel exome and targeted level sequencing 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.Journal of Investigative Dermatology accepted article preview online, 24 March 2014; doi:10.1038/jid.2014.154.

AB - Cutaneous SCC (cSCC) is the most frequent skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here we use massively parallel exome and targeted level sequencing 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.Journal of Investigative Dermatology accepted article preview online, 24 March 2014; doi:10.1038/jid.2014.154.

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DO - 10.1038/jid.2014.154

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JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 10

ER -

NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

Abstract

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Dermatology and Genetic Medicine (Strategic Grant) (Joint with Kings College London)

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Proby, Charlotte

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