Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

Peter Johansson; Lauren G Aoude; Karin Wadt; William J Glasson; Sunil K Warrier; Alex W Hewitt; Jens Folke Kiilgaard; Steffen Heegaard; Tim Isaacs; Maria Franchina; Christian Ingvar; Tersia Vermeulen; Kevin J Whitehead; Christopher W Schmidt; Jane M Palmer; Judith Symmons; Anne-Marie Gerdes; Göran Jönsson; Nicholas K Hayward

doi:10.18632/oncotarget.6614

Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

Peter Johansson, Lauren G Aoude, Karin Wadt, William J Glasson, Sunil K Warrier, Alex W Hewitt, Jens Folke Kiilgaard, Steffen Heegaard, Tim Isaacs, Maria Franchina, Christian Ingvar, Tersia Vermeulen, Kevin J Whitehead, Christopher W Schmidt, Jane M Palmer, Judith Symmons, Anne-Marie Gerdes, Göran Jönsson, Nicholas K Hayward

Institut for Klinisk Medicin

130 Citationer (Scopus)

Abstract

Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

Originalsprog	Engelsk
Tidsskrift	OncoTarget
Vol/bind	7
Udgave nummer	4
Sider (fra-til)	4624-31
Antal sider	8
ISSN	1949-2553
DOI	https://doi.org/10.18632/oncotarget.6614
Status	Udgivet - 2016

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10.18632/oncotarget.6614Licens: CC BY

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Johansson, P., Aoude, L. G., Wadt, K., Glasson, W. J., Warrier, S. K., Hewitt, A. W., Kiilgaard, J. F., Heegaard, S., Isaacs, T., Franchina, M., Ingvar, C., Vermeulen, T., Whitehead, K. J., Schmidt, C. W., Palmer, J. M., Symmons, J., Gerdes, A.-M., Jönsson, G., & Hayward, N. K. (2016). Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. OncoTarget, 7(4), 4624-31. https://doi.org/10.18632/oncotarget.6614

Johansson, P, Aoude, LG, Wadt, K, Glasson, WJ, Warrier, SK, Hewitt, AW, Kiilgaard, JF , Heegaard, S, Isaacs, T, Franchina, M, Ingvar, C, Vermeulen, T, Whitehead, KJ, Schmidt, CW, Palmer, JM, Symmons, J, Gerdes, A-M, Jönsson, G & Hayward, NK 2016, 'Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4', OncoTarget, bind 7, nr. 4, s. 4624-31. https://doi.org/10.18632/oncotarget.6614

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title = "Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4",

abstract = "Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.",

keywords = "Journal Article, Research Support, Non-U.S. Gov't",

author = "Peter Johansson and Aoude, {Lauren G} and Karin Wadt and Glasson, {William J} and Warrier, {Sunil K} and Hewitt, {Alex W} and Kiilgaard, {Jens Folke} and Steffen Heegaard and Tim Isaacs and Maria Franchina and Christian Ingvar and Tersia Vermeulen and Whitehead, {Kevin J} and Schmidt, {Christopher W} and Palmer, {Jane M} and Judith Symmons and Anne-Marie Gerdes and G{\"o}ran J{\"o}nsson and Hayward, {Nicholas K}",

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doi = "10.18632/oncotarget.6614",

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T1 - Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

AU - Johansson, Peter

AU - Aoude, Lauren G

AU - Wadt, Karin

AU - Glasson, William J

AU - Warrier, Sunil K

AU - Hewitt, Alex W

AU - Kiilgaard, Jens Folke

AU - Heegaard, Steffen

AU - Isaacs, Tim

AU - Franchina, Maria

AU - Ingvar, Christian

AU - Vermeulen, Tersia

AU - Whitehead, Kevin J

AU - Schmidt, Christopher W

AU - Palmer, Jane M

AU - Symmons, Judith

AU - Gerdes, Anne-Marie

AU - Jönsson, Göran

AU - Hayward, Nicholas K

PY - 2016

Y1 - 2016

N2 - Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

AB - Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.18632/oncotarget.6614

DO - 10.18632/oncotarget.6614

M3 - Journal article

C2 - 26683228

SN - 1949-2553

VL - 7

SP - 4624

EP - 4631

JO - OncoTarget

JF - OncoTarget

IS - 4

ER -

Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

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