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Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family

  1. Author:
    Brown, Kevin M
    Xu, Mai
    Sargen, Michael
    Jang,Hyunbum
    Zhang,Mingzhen
    Zhang, Tongwu
    Zhu, Bin
    Jones, Kristie
    Kim, Jung
    Mendoza, Laura
    Hayward, Nicholas K
    Tucker, Margaret A
    Goldstein, Alisa M
    Yang, Xiaohong Rose
    Stewart, Douglas R
    Hicks, Belynda
    Consonni, Dario
    Pesatori, Angela C
    Fargnoli, Maria Concetta
    Peris, Ketty
    Stratigos, Alex
    Menin, Chiara
    Ghiorzo, Paola
    Puig, Susana
    Nagore, Eduardo
    Andresson,Thorkell
    Nussinov,Ruth
    Calista, Donato
    Landi, Maria Teresa

  2. Author Address

    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, EPS 7106, Bethesda, MD, 20892, USA., Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia., Occupational Health Unit, Fondazione IRCCS Ca 39; Granda-Ospedale Maggiore Policlinico, Milan, Italy., Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy., Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L 39;Aquila, L 39;Aquila, Italy., Institute of Dermatology, Catholic University, Rome, Italy., Department of Dermatology, Andreas Syggros Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Immunology and Diagnostic Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, Genoa, Italy., Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy., Dermatology Department, Melanoma Unit, Hospital Cl 237;nic de Barcelona, IDIBAPS, Universitat de Barcelona, CIBERER, Barcelona, Spain., Department of Dermatology, Instituto Valenciano de Oncolog 237;a, Valencia, Spain., Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, EPS 7106, Bethesda, MD, 20892, USA. landim@mail.nih.gov.,
    1. Year: 2021
    2. Date: Jul 03
    3. Epub Date: 2021 07 03
  2. Journal: Familial cancer
  4. Type of Article: Article
  5. ISSN: 1389-9600
  1. Abstract:

    While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.

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External Sources

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  2. DOI: 10.1007/s10689-021-00267-9
  3. PMID: 34215961
  4. View record in Web of Science®
  5. WOS: 000669163600001
  6. PII : 10.1007/s10689-021-00267-9

Library Notes

  1. Fiscal Year: FY2020-2021
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