Melanoma genome sequencing reveals frequent PREX2 mutations

Michael F. Berger; Eran Hodis; Timothy P. Heffernan; Yonathan Lissanu Deribe; Michael S. Lawrence; Alexei Protopopov; Elena Ivanova; Ian R. Watson; Elizabeth Nickerson; Papia Ghosh; Hailei Zhang; Rhamy Zeid; Xiaojia Ren; Kristian Cibulskis; Andrey Y. Sivachenko; Nikhil Wagle; Antje Sucker; Carrie Sougnez; Robert Onofrio; Lauren Ambrogio; Daniel Auclair; Timothy Fennell; Scott L. Carter; Yotam Drier; Petar Stojanov; Meredith A. Singer; Douglas Voet; Rui Jing; Gordon Saksena; Jordi Barretina; Alex H. Ramos; Trevor J. Pugh; Nicolas Stransky; Melissa Parkin; Wendy Winckler; Scott Mahan; Kristin Ardlie; Jennifer Baldwin; Jennifer Wargo; Dirk Schadendorf; Matthew Meyerson; Stacey B. Gabriel; Todd R. Golub; Stephan N. Wagner; Eric S. Lander; Gad Getz; Lynda Chin; Levi A. Garraway

doi:10.1038/nature11071

Melanoma genome sequencing reveals frequent PREX2 mutations

Michael F. Berger, Eran Hodis, Timothy P. Heffernan, Yonathan Lissanu Deribe, Michael S. Lawrence, Alexei Protopopov, Elena Ivanova, Ian R. Watson, Elizabeth Nickerson, Papia Ghosh, Hailei Zhang, Rhamy Zeid, Xiaojia Ren, Kristian Cibulskis, Andrey Y. Sivachenko, Nikhil Wagle, Antje Sucker, Carrie Sougnez, Robert Onofrio, Lauren AmbrogioDaniel Auclair, Timothy Fennell, Scott L. Carter, Yotam Drier, Petar Stojanov, Meredith A. Singer, Douglas Voet, Rui Jing, Gordon Saksena, Jordi Barretina, Alex H. Ramos, Trevor J. Pugh, Nicolas Stransky, Melissa Parkin, Wendy Winckler, Scott Mahan, Kristin Ardlie, Jennifer Baldwin, Jennifer Wargo, Dirk Schadendorf, Matthew Meyerson, Stacey B. Gabriel, Todd R. Golub, Stephan N. Wagner, Eric S. Lander, Gad Getz, Lynda Chin, Levi A. Garraway

Genomic Medicine

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

587 Scopus citations

Abstract

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer-as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.

Original language	English (US)
Pages (from-to)	502-506
Number of pages	5
Journal	Nature
Volume	485
Issue number	7399
DOIs	https://doi.org/10.1038/nature11071
State	Published - May 24 2012

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Berger, M. F., Hodis, E., Heffernan, T. P., Deribe, Y. L., Lawrence, M. S., Protopopov, A., Ivanova, E., Watson, I. R., Nickerson, E., Ghosh, P., Zhang, H., Zeid, R., Ren, X., Cibulskis, K., Sivachenko, A. Y., Wagle, N., Sucker, A., Sougnez, C., Onofrio, R., ... Garraway, L. A. (2012). Melanoma genome sequencing reveals frequent PREX2 mutations. Nature, 485(7399), 502-506. https://doi.org/10.1038/nature11071

Berger, MF, Hodis, E, Heffernan, TP, Deribe, YL, Lawrence, MS, Protopopov, A, Ivanova, E, Watson, IR, Nickerson, E, Ghosh, P, Zhang, H, Zeid, R, Ren, X, Cibulskis, K, Sivachenko, AY, Wagle, N, Sucker, A, Sougnez, C, Onofrio, R, Ambrogio, L, Auclair, D, Fennell, T, Carter, SL, Drier, Y, Stojanov, P, Singer, MA, Voet, D, Jing, R, Saksena, G, Barretina, J, Ramos, AH, Pugh, TJ, Stransky, N, Parkin, M, Winckler, W, Mahan, S, Ardlie, K, Baldwin, J, Wargo, J, Schadendorf, D, Meyerson, M, Gabriel, SB, Golub, TR, Wagner, SN, Lander, ES, Getz, G, Chin, L & Garraway, LA 2012, 'Melanoma genome sequencing reveals frequent PREX2 mutations', Nature, vol. 485, no. 7399, pp. 502-506. https://doi.org/10.1038/nature11071

@article{908873541d2346d7828bef2637573cfa,

title = "Melanoma genome sequencing reveals frequent PREX2 mutations",

abstract = "Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer-as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.",

author = "Berger, {Michael F.} and Eran Hodis and Heffernan, {Timothy P.} and Deribe, {Yonathan Lissanu} and Lawrence, {Michael S.} and Alexei Protopopov and Elena Ivanova and Watson, {Ian R.} and Elizabeth Nickerson and Papia Ghosh and Hailei Zhang and Rhamy Zeid and Xiaojia Ren and Kristian Cibulskis and Sivachenko, {Andrey Y.} and Nikhil Wagle and Antje Sucker and Carrie Sougnez and Robert Onofrio and Lauren Ambrogio and Daniel Auclair and Timothy Fennell and Carter, {Scott L.} and Yotam Drier and Petar Stojanov and Singer, {Meredith A.} and Douglas Voet and Rui Jing and Gordon Saksena and Jordi Barretina and Ramos, {Alex H.} and Pugh, {Trevor J.} and Nicolas Stransky and Melissa Parkin and Wendy Winckler and Scott Mahan and Kristin Ardlie and Jennifer Baldwin and Jennifer Wargo and Dirk Schadendorf and Matthew Meyerson and Gabriel, {Stacey B.} and Golub, {Todd R.} and Wagner, {Stephan N.} and Lander, {Eric S.} and Gad Getz and Lynda Chin and Garraway, {Levi A.}",

note = "Funding Information: Acknowledgements Illumina sequencing was performed at the Broad Institute and array-based genomic characterization and functional studies were performed at the Belfer Institute of DFCI. We are grateful to the Broad Institute Genome Sequencing Platform, Genome Analysis Platform and Biological Samples Platform. This work was supported by the National Human Genome Research Institute (S.B.G., E.S.L.), National Cancer Institute (M.M., L.C.), FWF-Austrian Science Fund (S.N.W.), NIH Director{\textquoteright}s New Innovator Award (L.A.G.), Melanoma Research Alliance (L.A.G., L.C.), Starr Cancer Consortium (L.A.G.) and the Burroughs-Wellcome Fund (L.A.G.).",

year = "2012",

month = may,

day = "24",

doi = "10.1038/nature11071",

language = "English (US)",

volume = "485",

pages = "502--506",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7399",

}

TY - JOUR

T1 - Melanoma genome sequencing reveals frequent PREX2 mutations

AU - Berger, Michael F.

AU - Hodis, Eran

AU - Heffernan, Timothy P.

AU - Deribe, Yonathan Lissanu

AU - Lawrence, Michael S.

AU - Protopopov, Alexei

AU - Ivanova, Elena

AU - Watson, Ian R.

AU - Nickerson, Elizabeth

AU - Ghosh, Papia

AU - Zhang, Hailei

AU - Zeid, Rhamy

AU - Ren, Xiaojia

AU - Cibulskis, Kristian

AU - Sivachenko, Andrey Y.

AU - Wagle, Nikhil

AU - Sucker, Antje

AU - Sougnez, Carrie

AU - Onofrio, Robert

AU - Ambrogio, Lauren

AU - Auclair, Daniel

AU - Fennell, Timothy

AU - Carter, Scott L.

AU - Drier, Yotam

AU - Stojanov, Petar

AU - Singer, Meredith A.

AU - Voet, Douglas

AU - Jing, Rui

AU - Saksena, Gordon

AU - Barretina, Jordi

AU - Ramos, Alex H.

AU - Pugh, Trevor J.

AU - Stransky, Nicolas

AU - Parkin, Melissa

AU - Winckler, Wendy

AU - Mahan, Scott

AU - Ardlie, Kristin

AU - Baldwin, Jennifer

AU - Wargo, Jennifer

AU - Schadendorf, Dirk

AU - Meyerson, Matthew

AU - Gabriel, Stacey B.

AU - Golub, Todd R.

AU - Wagner, Stephan N.

AU - Lander, Eric S.

AU - Getz, Gad

AU - Chin, Lynda

AU - Garraway, Levi A.

N1 - Funding Information: Acknowledgements Illumina sequencing was performed at the Broad Institute and array-based genomic characterization and functional studies were performed at the Belfer Institute of DFCI. We are grateful to the Broad Institute Genome Sequencing Platform, Genome Analysis Platform and Biological Samples Platform. This work was supported by the National Human Genome Research Institute (S.B.G., E.S.L.), National Cancer Institute (M.M., L.C.), FWF-Austrian Science Fund (S.N.W.), NIH Director’s New Innovator Award (L.A.G.), Melanoma Research Alliance (L.A.G., L.C.), Starr Cancer Consortium (L.A.G.) and the Burroughs-Wellcome Fund (L.A.G.).

PY - 2012/5/24

Y1 - 2012/5/24

N2 - Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer-as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.

AB - Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer-as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.

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UR - http://www.scopus.com/inward/citedby.url?scp=84861427327&partnerID=8YFLogxK

U2 - 10.1038/nature11071

DO - 10.1038/nature11071

M3 - Article

C2 - 22622578

AN - SCOPUS:84861427327

SN - 0028-0836

VL - 485

SP - 502

EP - 506

JO - Nature

JF - Nature

IS - 7399

ER -

Melanoma genome sequencing reveals frequent PREX2 mutations

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