EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas

Dariush Etemadmoghadam; Walid J. Azar; Ying Lei; Tania Moujaber; Dale W. Garsed; Catherine J. Kennedy; Sian Fereday; Chris Mitchell; Yoke-Eng Chiew; Joy Hendley; Raghwa Sharma; Paul R. Harnett; Jason Li; Elizabeth L. Christie; Ann Marie Patch; Joshy George; George Au-Yeung; Gisela Mir Arnau; Timothy P. Holloway; Timothy Semple; John V. Pearson; Nicola Waddell; Sean M. Grimmond; Martin Köbel; Helen Rizos; Ivan B. Lomakin; David D.L. Bowtell; Anna deFazio

doi:10.1158/0008-5472.CAN-16-2224

EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas

Dariush Etemadmoghadam, Walid J. Azar, Ying Lei, Tania Moujaber, Dale W. Garsed, Catherine J. Kennedy, Sian Fereday, Chris Mitchell, Yoke-Eng Chiew, Joy Hendley, Raghwa Sharma, Paul R. Harnett, Jason Li, Elizabeth L. Christie, Ann Marie Patch, Joshy George, George Au-Yeung, Gisela Mir Arnau, Timothy P. Holloway, Timothy SempleJohn V. Pearson, Nicola Waddell, Sean M. Grimmond, Martin Köbel, Helen Rizos, Ivan B. Lomakin, David D.L. Bowtell^*, Anna deFazio

^*Corresponding author for this work

Faculty of Medicine, Health and Human Sciences

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

41 Citations (Scopus)

Abstract

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer.

Original language	English
Pages (from-to)	4268-4278
Number of pages	11
Journal	Cancer Research
Volume	77
Issue number	16
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-2224
Publication status	Published - 15 Aug 2017

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10.1158/0008-5472.CAN-16-2224

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Etemadmoghadam, D., Azar, W. J., Lei, Y., Moujaber, T., Garsed, D. W., Kennedy, C. J., Fereday, S., Mitchell, C., Chiew, Y-E., Hendley, J., Sharma, R., Harnett, P. R., Li, J., Christie, E. L., Patch, A. M., George, J., Au-Yeung, G., Arnau, G. M., Holloway, T. P., ... deFazio, A. (2017). EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas. Cancer Research, 77(16), 4268-4278. https://doi.org/10.1158/0008-5472.CAN-16-2224

Etemadmoghadam, Dariush ; Azar, Walid J. ; Lei, Ying ; Moujaber, Tania ; Garsed, Dale W. ; Kennedy, Catherine J. ; Fereday, Sian ; Mitchell, Chris ; Chiew, Yoke-Eng ; Hendley, Joy ; Sharma, Raghwa ; Harnett, Paul R. ; Li, Jason ; Christie, Elizabeth L. ; Patch, Ann Marie ; George, Joshy ; Au-Yeung, George ; Arnau, Gisela Mir ; Holloway, Timothy P. ; Semple, Timothy ; Pearson, John V. ; Waddell, Nicola ; Grimmond, Sean M. ; Köbel, Martin ; Rizos, Helen ; Lomakin, Ivan B. ; Bowtell, David D.L. ; deFazio, Anna. / EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas. In: Cancer Research. 2017 ; Vol. 77, No. 16. pp. 4268-4278.

@article{d73b0cf34b224760afaff1f50b2c804f,

title = "EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas",

abstract = "Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer.",

author = "Dariush Etemadmoghadam and Azar, {Walid J.} and Ying Lei and Tania Moujaber and Garsed, {Dale W.} and Kennedy, {Catherine J.} and Sian Fereday and Chris Mitchell and Yoke-Eng Chiew and Joy Hendley and Raghwa Sharma and Harnett, {Paul R.} and Jason Li and Christie, {Elizabeth L.} and Patch, {Ann Marie} and Joshy George and George Au-Yeung and Arnau, {Gisela Mir} and Holloway, {Timothy P.} and Timothy Semple and Pearson, {John V.} and Nicola Waddell and Grimmond, {Sean M.} and Martin K{\"o}bel and Helen Rizos and Lomakin, {Ivan B.} and Bowtell, {David D.L.} and Anna deFazio",

year = "2017",

month = aug,

day = "15",

doi = "10.1158/0008-5472.CAN-16-2224",

language = "English",

volume = "77",

pages = "4268--4278",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research",

number = "16",

}

Etemadmoghadam, D, Azar, WJ, Lei, Y, Moujaber, T, Garsed, DW, Kennedy, CJ, Fereday, S, Mitchell, C, Chiew, Y-E, Hendley, J, Sharma, R, Harnett, PR, Li, J, Christie, EL, Patch, AM, George, J, Au-Yeung, G, Arnau, GM, Holloway, TP, Semple, T, Pearson, JV, Waddell, N, Grimmond, SM, Köbel, M, Rizos, H, Lomakin, IB, Bowtell, DDL & deFazio, A 2017, 'EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas', Cancer Research, vol. 77, no. 16, pp. 4268-4278. https://doi.org/10.1158/0008-5472.CAN-16-2224

EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas. / Etemadmoghadam, Dariush; Azar, Walid J.; Lei, Ying; Moujaber, Tania; Garsed, Dale W.; Kennedy, Catherine J.; Fereday, Sian; Mitchell, Chris; Chiew, Yoke-Eng; Hendley, Joy; Sharma, Raghwa; Harnett, Paul R.; Li, Jason; Christie, Elizabeth L.; Patch, Ann Marie; George, Joshy; Au-Yeung, George; Arnau, Gisela Mir; Holloway, Timothy P.; Semple, Timothy; Pearson, John V.; Waddell, Nicola; Grimmond, Sean M.; Köbel, Martin; Rizos, Helen; Lomakin, Ivan B.; Bowtell, David D.L.; deFazio, Anna.

In: Cancer Research, Vol. 77, No. 16, 15.08.2017, p. 4268-4278.

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

TY - JOUR

T1 - EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas

AU - Etemadmoghadam, Dariush

AU - Azar, Walid J.

AU - Lei, Ying

AU - Moujaber, Tania

AU - Garsed, Dale W.

AU - Kennedy, Catherine J.

AU - Fereday, Sian

AU - Mitchell, Chris

AU - Chiew, Yoke-Eng

AU - Hendley, Joy

AU - Sharma, Raghwa

AU - Harnett, Paul R.

AU - Li, Jason

AU - Christie, Elizabeth L.

AU - Patch, Ann Marie

AU - George, Joshy

AU - Au-Yeung, George

AU - Arnau, Gisela Mir

AU - Holloway, Timothy P.

AU - Semple, Timothy

AU - Pearson, John V.

AU - Waddell, Nicola

AU - Grimmond, Sean M.

AU - Köbel, Martin

AU - Rizos, Helen

AU - Lomakin, Ivan B.

AU - Bowtell, David D.L.

AU - deFazio, Anna

PY - 2017/8/15

Y1 - 2017/8/15

N2 - Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer.

AB - Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer.

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U2 - 10.1158/0008-5472.CAN-16-2224

DO - 10.1158/0008-5472.CAN-16-2224

M3 - Article

C2 - 28646021

AN - SCOPUS:85028300885

VL - 77

SP - 4268

EP - 4278

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 16

ER -

EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas

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