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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista


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.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
RivistaFamilial Cancer
Stato di pubblicazionePubblicato - 2021


  • Familial cancer
  • In vitro characterization
  • Melanoma
  • Molecular modeling
  • NRAS gene
  • Rare variant


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