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Title: Whole-genome landscapes of major melanoma subtypes

Abstract

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. We report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. But, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. In most cases, melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated tomore » sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [3];  [3];  [6]; ORCiD logo [7];  [8];  [8];  [3];  [3];  [3];  [9];  [9];  [3];  [3];  [10];  [11] more »;  [11];  [6];  [6];  [6];  [12];  [13];  [11];  [4];  [4];  [4];  [14];  [14];  [15];  [12];  [16];  [8];  [17];  [18];  [19];  [20];  [17];  [21];  [8];  [8];  [22];  [3];  [8];  [23];  [24] « less
  1. Univ. of Sydney, NSW (Australia). Melanoma Inst. Australia; QIMR Berghofer Medical Research Inst., Queensland (Australia)
  2. Univ. of Sydney, NSW (Australia). Melanoma Inst. Australia; Univ. of Sydney, NSW (Australia). Sydney Medical School
  3. QIMR Berghofer Medical Research Inst., Queensland (Australia); Univ. of Queensland, Brisbane (Australia). Inst. for Molecular Bioscience
  4. QIMR Berghofer Medical Research Inst., Queensland (Australia)
  5. James Collk Univ., Queensland (Australia). Australian Inst. of Tropical Health and Medicine
  6. Univ. of Sydney, NSW (Australia). Sydney Medical School
  7. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  8. Univ. of Sydney, NSW (Australia). Melanoma Inst. Australia
  9. Barcelona Inst. of Science and Technology, Barcelona (Spain). Inst. for Research in Biomedicine (IRB Barcelona)
  10. Univ. of Queensland, Brisbane (Australia). Inst. for Molecular Bioscience
  11. Univ. of Sydney, NSW (Australia). Westmead Inst. for Medical Research
  12. Univ. of Sydney, NSW (Australia). Children's Medical Research Inst.
  13. Univ. of Sydney, NSW (Australia). Children's Hospital at Westmead
  14. Bioplatforms Australia, NSW (Australia)
  15. Univ. of Melbourne (Australia). University of Melbourne Centre for Cancer Research
  16. Univ. of Sydney, NSW (Australia). School of Mathematics and Statistics
  17. La Trobe Univ., Melbourne, VIC (Australia). Olivia Newton-John Cancer Research Inst.
  18. Univ. of Sydney, NSW (Australia). Melanoma Inst. Australia; Macquarie Univ., NSW (Australia)
  19. Univ. of Sydney, NSW (Australia). Melanoma Inst. Australia; Univ. of Sydney, NSW (Australia). Centenary Inst.
  20. Univ. of Sydney, NSW (Australia). Melanoma Inst. Australia; Royal North Short Hospital, NSW (Australia). Dept. of Medical Oncology
  21. Peter MacCallum Cancer Centre and Univ. of Melbourne (Australia)
  22. Barcelona Inst. of Science and Technology, Barcelona (Spain). Inst. for Research in Biomedicine (IRB Barcelona); Catalana Inst. of Research and Advanced Studies (ICREA), Barcelona (Spain)
  23. Univ. of Sydney, NSW (Australia). Melanoma Inst. Australia; Univ. of Sydney, NSW (Australia). Sydney Medical School; Royal Prince Alfred Hospital, NSW (Australia). Tissue Pathology and Diagnostic Oncology
  24. Univ. of Sydney, NSW (Australia). Melanoma Inst. Australia; Univ. of Sydney, NSW (Australia). Westmead Inst. for Medical Research
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1357116
Report Number(s):
LA-UR-16-21896
Journal ID: ISSN 0028-0836
Grant/Contract Number:
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 545; Journal Issue: 7653; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Biological Science

Citation Formats

Hayward, Nicholas K., Wilmott, James S., Waddell, Nicola, Johansson, Peter A., Field, Matthew A., Nones, Katia, Patch, Ann-Marie, Kakavand, Hojabr, Alexandrov, Ludmil B., Burke, Hazel, Jakrot, Valerie, Kazakoff, Stephen, Holmes, Oliver, Leonard, Conrad, Sabarinathan, Radhakrishnan, Mularoni, Loris, Wood, Scott, Xu, Qinying, Waddell, Nick, Tembe, Varsha, Pupo, Gulietta M., De Paoli-Iseppi, Ricardo, Vilain, Ricardo E., Shang, Ping, Lau, Loretta M. S., Dagg, Rebecca A., Schramm, Sarah-Jane, Pritchard, Antonia, Dutton-Regester, Ken, Newell, Felicity, Fitzgerald, Anna, Shang, Catherine A., Grimmond, Sean M., Pickett, Hilda A., Yang, Jean Y., Stretch, Jonathan R., Behren, Andreas, Kefford, Richard F., Hersey, Peter, Long, Georgina V., Cebon, Jonathan, Shackleton, Mark, Spillane, Andrew J., Saw, Robyn P. M., López-Bigas, Núria, Pearson, John V., Thompson, John F., Scolyer, Richard A., and Mann, Graham J. Whole-genome landscapes of major melanoma subtypes. United States: N. p., 2017. Web. doi:10.1038/nature22071.
Hayward, Nicholas K., Wilmott, James S., Waddell, Nicola, Johansson, Peter A., Field, Matthew A., Nones, Katia, Patch, Ann-Marie, Kakavand, Hojabr, Alexandrov, Ludmil B., Burke, Hazel, Jakrot, Valerie, Kazakoff, Stephen, Holmes, Oliver, Leonard, Conrad, Sabarinathan, Radhakrishnan, Mularoni, Loris, Wood, Scott, Xu, Qinying, Waddell, Nick, Tembe, Varsha, Pupo, Gulietta M., De Paoli-Iseppi, Ricardo, Vilain, Ricardo E., Shang, Ping, Lau, Loretta M. S., Dagg, Rebecca A., Schramm, Sarah-Jane, Pritchard, Antonia, Dutton-Regester, Ken, Newell, Felicity, Fitzgerald, Anna, Shang, Catherine A., Grimmond, Sean M., Pickett, Hilda A., Yang, Jean Y., Stretch, Jonathan R., Behren, Andreas, Kefford, Richard F., Hersey, Peter, Long, Georgina V., Cebon, Jonathan, Shackleton, Mark, Spillane, Andrew J., Saw, Robyn P. M., López-Bigas, Núria, Pearson, John V., Thompson, John F., Scolyer, Richard A., & Mann, Graham J. Whole-genome landscapes of major melanoma subtypes. United States. doi:10.1038/nature22071.
Hayward, Nicholas K., Wilmott, James S., Waddell, Nicola, Johansson, Peter A., Field, Matthew A., Nones, Katia, Patch, Ann-Marie, Kakavand, Hojabr, Alexandrov, Ludmil B., Burke, Hazel, Jakrot, Valerie, Kazakoff, Stephen, Holmes, Oliver, Leonard, Conrad, Sabarinathan, Radhakrishnan, Mularoni, Loris, Wood, Scott, Xu, Qinying, Waddell, Nick, Tembe, Varsha, Pupo, Gulietta M., De Paoli-Iseppi, Ricardo, Vilain, Ricardo E., Shang, Ping, Lau, Loretta M. S., Dagg, Rebecca A., Schramm, Sarah-Jane, Pritchard, Antonia, Dutton-Regester, Ken, Newell, Felicity, Fitzgerald, Anna, Shang, Catherine A., Grimmond, Sean M., Pickett, Hilda A., Yang, Jean Y., Stretch, Jonathan R., Behren, Andreas, Kefford, Richard F., Hersey, Peter, Long, Georgina V., Cebon, Jonathan, Shackleton, Mark, Spillane, Andrew J., Saw, Robyn P. M., López-Bigas, Núria, Pearson, John V., Thompson, John F., Scolyer, Richard A., and Mann, Graham J. Wed . "Whole-genome landscapes of major melanoma subtypes". United States. doi:10.1038/nature22071. https://www.osti.gov/servlets/purl/1357116.
@article{osti_1357116,
title = {Whole-genome landscapes of major melanoma subtypes},
author = {Hayward, Nicholas K. and Wilmott, James S. and Waddell, Nicola and Johansson, Peter A. and Field, Matthew A. and Nones, Katia and Patch, Ann-Marie and Kakavand, Hojabr and Alexandrov, Ludmil B. and Burke, Hazel and Jakrot, Valerie and Kazakoff, Stephen and Holmes, Oliver and Leonard, Conrad and Sabarinathan, Radhakrishnan and Mularoni, Loris and Wood, Scott and Xu, Qinying and Waddell, Nick and Tembe, Varsha and Pupo, Gulietta M. and De Paoli-Iseppi, Ricardo and Vilain, Ricardo E. and Shang, Ping and Lau, Loretta M. S. and Dagg, Rebecca A. and Schramm, Sarah-Jane and Pritchard, Antonia and Dutton-Regester, Ken and Newell, Felicity and Fitzgerald, Anna and Shang, Catherine A. and Grimmond, Sean M. and Pickett, Hilda A. and Yang, Jean Y. and Stretch, Jonathan R. and Behren, Andreas and Kefford, Richard F. and Hersey, Peter and Long, Georgina V. and Cebon, Jonathan and Shackleton, Mark and Spillane, Andrew J. and Saw, Robyn P. M. and López-Bigas, Núria and Pearson, John V. and Thompson, John F. and Scolyer, Richard A. and Mann, Graham J.},
abstractNote = {Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. We report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. But, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. In most cases, melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.},
doi = {10.1038/nature22071},
journal = {Nature (London)},
number = 7653,
volume = 545,
place = {United States},
year = {Wed May 03 00:00:00 EDT 2017},
month = {Wed May 03 00:00:00 EDT 2017}
}

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  • The grassland and shrubland are two major landscapes of the Tibetan alpine meadow, a region very sensitive to the impact of global warming and anthropogenic perturbation. Herein, we report a study showing that a majority of differences in soil microbial community functional structures, measured by a functional gene array named GeoChip 4.0, in two adjacent shrubland and grassland areas, were explainable by environmental properties, suggesting that the harsh environments in the alpine grassland rendered niche adaptation important. Furthermore, genes involved in labile carbon degradation were more abundant in the shrubland than those of the grassland but genes involved in recalcitrantmore » carbon degradation were less abundant, which was conducive to long-term carbon storage and sequestration in the shrubland despite low soil organic carbon content. In addition, genes of anerobic nitrogen cycling processes such as denitrification and dissimilatory nitrogen reduction were more abundant, shifting soil nitrogen cycling toward ammonium biosynthesis and consequently leading to higher soil ammonium contents. In conclusion, we also noted higher abundances of stress genes responsive to nitrogen limitation and oxygen limitation, which might be attributed to low total nitrogen and higher water contents in the shrubland. Together, these results provide mechanistic knowledge about microbial linkages to soil carbon and nitrogen storage and potential consequences of vegetation shifts in the Tibetan alpine meadow.« less