Whole exome sequencing of adenoid cystic carcinoma

Philip J. Stephens; Helen R. Davies; Yoshitsugu Mitani; Peter Van Loo; Adam Shlien; Patrick S. Tarpey; Elli Papaemmanuil; Angela Cheverton; Graham R. Bignell; Adam P. Butler; John Gamble; Stephen Gamble; Claire Hardy; Jonathan Hinton; Mingming Jia; Alagu Jayakumar; David Jones; Calli Latimer; Stuart McLaren; David J. McBride; Andrew Menzies; Laura Mudie; Mark Maddison; Keiran Raine; Serena Nik-Zainal; Sarah O'Meara; Jon W. Teague; Ignacio Varela; David C. Wedge; Ian Whitmore; Scott M. Lippman; Ultan McDermott; Michael R. Stratton; Peter J. Campbell; Adel K. El-Naggar; P. Andrew Futreal

doi:10.1172/JCI67201

Whole exome sequencing of adenoid cystic carcinoma

Philip J. Stephens, Helen R. Davies, Yoshitsugu Mitani, Peter Van Loo, Adam Shlien, Patrick S. Tarpey, Elli Papaemmanuil, Angela Cheverton, Graham R. Bignell, Adam P. Butler, John Gamble, Stephen Gamble, Claire Hardy, Jonathan Hinton, Mingming Jia, Alagu Jayakumar, David Jones, Calli Latimer, Stuart McLaren, David J. McBrideAndrew Menzies, Laura Mudie, Mark Maddison, Keiran Raine, Serena Nik-Zainal, Sarah O'Meara, Jon W. Teague, Ignacio Varela, David C. Wedge, Ian Whitmore, Scott M. Lippman, Ultan McDermott, Michael R. Stratton, Peter J. Campbell, Adel K. El-Naggar, P. Andrew Futreal

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

215 Scopus citations

Abstract

Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.

Original language	English (US)
Pages (from-to)	2965-2968
Number of pages	4
Journal	Journal of Clinical Investigation
Volume	123
Issue number	7
DOIs	https://doi.org/10.1172/JCI67201
State	Published - Jul 1 2013

ASJC Scopus subject areas

General Medicine

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Stephens, P. J., Davies, H. R., Mitani, Y., Van Loo, P., Shlien, A., Tarpey, P. S., Papaemmanuil, E., Cheverton, A., Bignell, G. R., Butler, A. P., Gamble, J., Gamble, S., Hardy, C., Hinton, J., Jia, M., Jayakumar, A., Jones, D., Latimer, C., McLaren, S., ... Futreal, P. A. (2013). Whole exome sequencing of adenoid cystic carcinoma. Journal of Clinical Investigation, 123(7), 2965-2968. https://doi.org/10.1172/JCI67201

Stephens, PJ, Davies, HR, Mitani, Y, Van Loo, P, Shlien, A, Tarpey, PS, Papaemmanuil, E, Cheverton, A, Bignell, GR, Butler, AP, Gamble, J, Gamble, S, Hardy, C, Hinton, J, Jia, M, Jayakumar, A, Jones, D, Latimer, C, McLaren, S, McBride, DJ, Menzies, A, Mudie, L, Maddison, M, Raine, K, Nik-Zainal, S, O'Meara, S, Teague, JW, Varela, I, Wedge, DC, Whitmore, I, Lippman, SM, McDermott, U, Stratton, MR, Campbell, PJ, El-Naggar, AK & Futreal, PA 2013, 'Whole exome sequencing of adenoid cystic carcinoma', Journal of Clinical Investigation, vol. 123, no. 7, pp. 2965-2968. https://doi.org/10.1172/JCI67201

@article{d58cbb0e0fcb476ba850bf27cf66fe5a,

title = "Whole exome sequencing of adenoid cystic carcinoma",

abstract = "Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.",

author = "Stephens, {Philip J.} and Davies, {Helen R.} and Yoshitsugu Mitani and {Van Loo}, Peter and Adam Shlien and Tarpey, {Patrick S.} and Elli Papaemmanuil and Angela Cheverton and Bignell, {Graham R.} and Butler, {Adam P.} and John Gamble and Stephen Gamble and Claire Hardy and Jonathan Hinton and Mingming Jia and Alagu Jayakumar and David Jones and Calli Latimer and Stuart McLaren and McBride, {David J.} and Andrew Menzies and Laura Mudie and Mark Maddison and Keiran Raine and Serena Nik-Zainal and Sarah O'Meara and Teague, {Jon W.} and Ignacio Varela and Wedge, {David C.} and Ian Whitmore and Lippman, {Scott M.} and Ultan McDermott and Stratton, {Michael R.} and Campbell, {Peter J.} and El-Naggar, {Adel K.} and Futreal, {P. Andrew}",

year = "2013",

month = jul,

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doi = "10.1172/JCI67201",

language = "English (US)",

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T1 - Whole exome sequencing of adenoid cystic carcinoma

AU - Stephens, Philip J.

AU - Davies, Helen R.

AU - Mitani, Yoshitsugu

AU - Van Loo, Peter

AU - Shlien, Adam

AU - Tarpey, Patrick S.

AU - Papaemmanuil, Elli

AU - Cheverton, Angela

AU - Bignell, Graham R.

AU - Butler, Adam P.

AU - Gamble, John

AU - Gamble, Stephen

AU - Hardy, Claire

AU - Hinton, Jonathan

AU - Jia, Mingming

AU - Jayakumar, Alagu

AU - Jones, David

AU - Latimer, Calli

AU - McLaren, Stuart

AU - McBride, David J.

AU - Menzies, Andrew

AU - Mudie, Laura

AU - Maddison, Mark

AU - Raine, Keiran

AU - Nik-Zainal, Serena

AU - O'Meara, Sarah

AU - Teague, Jon W.

AU - Varela, Ignacio

AU - Wedge, David C.

AU - Whitmore, Ian

AU - Lippman, Scott M.

AU - McDermott, Ultan

AU - Stratton, Michael R.

AU - Campbell, Peter J.

AU - El-Naggar, Adel K.

AU - Futreal, P. Andrew

PY - 2013/7/1

Y1 - 2013/7/1

N2 - Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.

AB - Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.

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DO - 10.1172/JCI67201

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SP - 2965

EP - 2968

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 7

ER -

Whole exome sequencing of adenoid cystic carcinoma

Abstract

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