Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets

Felicity Newell; Yan Kong; James S. Wilmott; Peter A. Johansson; Peter M. Ferguson; Chuanliang Cui; Zhongwu Li; Stephen H. Kazakoff; Hazel Burke; Tristan J. Dodds; Ann Marie Patch; Katia Nones; Varsha Tembe; Ping Shang; Louise van der Weyden; Kim Wong; Oliver Holmes; Serigne Lo; Conrad Leonard; Scott Wood; Qinying Xu; Robert V. Rawson; Pamela Mukhopadhyay; Reinhard Dummer; Mitchell P. Levesque; Göran Jönsson; Xuan Wang; Iwei Yeh; Hong Wu; Nancy Joseph; Boris C. Bastian; Georgina V. Long; Andrew J. Spillane; Kerwin F. Shannon; John F. Thompson; Robyn P.M. Saw; David J. Adams; Lu Si; John V. Pearson; Nicholas K. Hayward; Nicola Waddell; Graham J. Mann; Jun Guo; Richard A. Scolyer

doi:10.1038/s41467-019-11107-x

Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets

Felicity Newell, Yan Kong, James S. Wilmott, Peter A. Johansson, Peter M. Ferguson, Chuanliang Cui, Zhongwu Li, Stephen H. Kazakoff, Hazel Burke, Tristan J. Dodds, Ann Marie Patch, Katia Nones, Varsha Tembe, Ping Shang, Louise van der Weyden, Kim Wong, Oliver Holmes, Serigne Lo, Conrad Leonard, Scott WoodQinying Xu, Robert V. Rawson, Pamela Mukhopadhyay, Reinhard Dummer, Mitchell P. Levesque, Göran Jönsson, Xuan Wang, Iwei Yeh, Hong Wu, Nancy Joseph, Boris C. Bastian, Georgina V. Long, Andrew J. Spillane, Kerwin F. Shannon, John F. Thompson, Robyn P.M. Saw, David J. Adams, Lu Si, John V. Pearson, Nicholas K. Hayward, Nicola Waddell, Graham J. Mann, Jun Guo, Richard A. Scolyer^*

^*Corresponding author for this work

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

208 Citations (Scopus)

Abstract

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

Original language	English
Article number	3163
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11107-x
Publication status	Published - 1 Dec 2019
Externally published	Yes

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Newell, F., Kong, Y., Wilmott, J. S., Johansson, P. A., Ferguson, P. M., Cui, C., Li, Z., Kazakoff, S. H., Burke, H., Dodds, T. J., Patch, A. M., Nones, K., Tembe, V., Shang, P., van der Weyden, L., Wong, K., Holmes, O., Lo, S., Leonard, C., ... Scolyer, R. A. (2019). Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets. Nature Communications, 10(1), Article 3163. https://doi.org/10.1038/s41467-019-11107-x

@article{07354b408fa9481ab637379b0aaffeb6,

title = "Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets",

abstract = "Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.",

author = "Felicity Newell and Yan Kong and Wilmott, {James S.} and Johansson, {Peter A.} and Ferguson, {Peter M.} and Chuanliang Cui and Zhongwu Li and Kazakoff, {Stephen H.} and Hazel Burke and Dodds, {Tristan J.} and Patch, {Ann Marie} and Katia Nones and Varsha Tembe and Ping Shang and {van der Weyden}, Louise and Kim Wong and Oliver Holmes and Serigne Lo and Conrad Leonard and Scott Wood and Qinying Xu and Rawson, {Robert V.} and Pamela Mukhopadhyay and Reinhard Dummer and Levesque, {Mitchell P.} and G{\"o}ran J{\"o}nsson and Xuan Wang and Iwei Yeh and Hong Wu and Nancy Joseph and Bastian, {Boris C.} and Long, {Georgina V.} and Spillane, {Andrew J.} and Shannon, {Kerwin F.} and Thompson, {John F.} and Saw, {Robyn P.M.} and Adams, {David J.} and Lu Si and Pearson, {John V.} and Hayward, {Nicholas K.} and Nicola Waddell and Mann, {Graham J.} and Jun Guo and Scolyer, {Richard A.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-11107-x",

language = "English",

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Newell, F, Kong, Y, Wilmott, JS, Johansson, PA, Ferguson, PM, Cui, C, Li, Z, Kazakoff, SH, Burke, H, Dodds, TJ, Patch, AM, Nones, K, Tembe, V, Shang, P, van der Weyden, L, Wong, K, Holmes, O, Lo, S, Leonard, C, Wood, S, Xu, Q, Rawson, RV, Mukhopadhyay, P, Dummer, R, Levesque, MP, Jönsson, G, Wang, X, Yeh, I, Wu, H, Joseph, N, Bastian, BC, Long, GV, Spillane, AJ, Shannon, KF, Thompson, JF, Saw, RPM, Adams, DJ, Si, L, Pearson, JV, Hayward, NK, Waddell, N, Mann, GJ, Guo, J & Scolyer, RA 2019, 'Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets', Nature Communications, vol. 10, no. 1, 3163. https://doi.org/10.1038/s41467-019-11107-x

TY - JOUR

T1 - Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets

AU - Newell, Felicity

AU - Kong, Yan

AU - Wilmott, James S.

AU - Johansson, Peter A.

AU - Ferguson, Peter M.

AU - Cui, Chuanliang

AU - Li, Zhongwu

AU - Kazakoff, Stephen H.

AU - Burke, Hazel

AU - Dodds, Tristan J.

AU - Patch, Ann Marie

AU - Nones, Katia

AU - Tembe, Varsha

AU - Shang, Ping

AU - van der Weyden, Louise

AU - Wong, Kim

AU - Holmes, Oliver

AU - Lo, Serigne

AU - Leonard, Conrad

AU - Wood, Scott

AU - Xu, Qinying

AU - Rawson, Robert V.

AU - Mukhopadhyay, Pamela

AU - Dummer, Reinhard

AU - Levesque, Mitchell P.

AU - Jönsson, Göran

AU - Wang, Xuan

AU - Yeh, Iwei

AU - Wu, Hong

AU - Joseph, Nancy

AU - Bastian, Boris C.

AU - Long, Georgina V.

AU - Spillane, Andrew J.

AU - Shannon, Kerwin F.

AU - Thompson, John F.

AU - Saw, Robyn P.M.

AU - Adams, David J.

AU - Si, Lu

AU - Pearson, John V.

AU - Hayward, Nicholas K.

AU - Waddell, Nicola

AU - Mann, Graham J.

AU - Guo, Jun

AU - Scolyer, Richard A.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

AB - Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

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U2 - 10.1038/s41467-019-11107-x

DO - 10.1038/s41467-019-11107-x

M3 - Article

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3163

ER -

Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets

Abstract

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