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Ref Type Journal Article
PMID (22197931)
Authors Nikolaev SI, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, Harshman K, Guipponi M, Bukach O, Zoete V, Michielin O, Muehlethaler K, Speiser D, Beckmann JS, Xenarios I, Halazonetis TD, Jongeneel CV, Stevenson BJ, Antonarakis SE
Title Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.
Abstract Text We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BRIP1 S624L missense unknown BRIP1 S624L does not lie within any known functional domains of the Brip1 protein ( S624L has been identified in sequencing studies (PMID: 27978560, PMID: 22810696, PMID: 22197931), but has not been biochemically characterized and therefore, its effect on Brip1 protein function is unknown (PubMed, Mar 2024).
MAP2K1 E203K missense gain of function MAP2K1 E203K lies within the protein kinase domain of the Map2k1 protein ( E203K confers a gain of function to the Map2k1 protein as demonstrated by constitutive Erk phosphorylation (PMID: 22197931, PMID: 29483135) and cell transformation in culture (PMID: 22197931), and is associated with drug resistance in the context of BRAF V600E in culture (PMID: 28986383). Y
MAP2K1 N382H missense no effect - predicted MAP2K1 N382H does not lie within any known functional domains of the Map2k1 protein ( N382H does not induce Erk phosphorylation in cultured cells (PMID: 22197931) and results in slower cell proliferation compared to wild-type Map2k1 in culture (PMID: 36442478), and therefore, is predicted to have no effect on Map2k1 protein function.
MAP2K1 P124S missense unknown MAP2K1 P124S lies within the protein kinase domain of the Map2k1 protein ( P124S results in increased Erk1/2 phosphorylation and confers resistance to Mek and Braf inhibitors (PMID: 19915144, PMID: 22197931) and an Egfr antibody (PMID: 33322618) in culture, but has similar induction of cell proliferation and viability levels to wild-type Map2k1 in culture (PMID: 29533785), and therefore, its effect on Map2k1 protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E MAP2K1 P124S melanoma decreased response Selumetinib Preclinical - Patient cell culture Actionable In a preclinical study, patient-derived melanoma cells harboring BRAF V600E and MAP2K1 P124S demonstrated decreased sensitivity to Selumetinib (AZD6244) compared to cells harboring BRAF V600E alone in culture (PMID: 22197931). 22197931