Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4
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Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. / Johansson, Peter; Aoude, Lauren G; Wadt, Karin; Glasson, William J; Warrier, Sunil K; Hewitt, Alex W; Kiilgaard, Jens Folke; Heegaard, Steffen; Isaacs, Tim; Franchina, Maria; Ingvar, Christian; Vermeulen, Tersia; Whitehead, Kevin J; Schmidt, Christopher W; Palmer, Jane M; Symmons, Judith; Gerdes, Anne-Marie; Jönsson, Göran; Hayward, Nicholas K.
I: OncoTarget, Bind 7, Nr. 4, 2016, s. 4624-31.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
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
VL - 7
SP - 4624
EP - 4631
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 4
ER -
ID: 164532665