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

Autor: Jung Kim, Ketty Peris, Kristie Jones, Eduardo Nagore, Alex Stratigos, Paola Ghiorzo, Bin Zhu, Kevin M. Brown, Belynda Hicks, Mai Xu, Hyunbum Jang, Donato Calista, Dario Consonni, Laura Mendoza, Ruth Nussinov, Douglas R. Stewart, Maria Teresa Landi, Xiaohong Rose Yang, Mingzhen Zhang, Nicholas K. Hayward, Thorkell Andresson, Chiara Menin, Maria Concetta Fargnoli, Michael R. Sargen, Alisa M. Goldstein, Margaret A. Tucker, Susana Puig, Angela Cecilia Pesatori, Tongwu Zhang
Rok vydání: 2021
Předmět:
Zdroj: Fam Cancer
ISSN: 1573-7292
1389-9600
DOI: 10.1007/s10689-021-00267-9
Popis: 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 a 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.
Databáze: OpenAIRE
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