Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature genetics	44	2	2012 Feb	133-9	Nat Genet

URL

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
MAP2K1	E203K	missense	gain of function	MAP2K1 E203K lies within the protein kinase domain of the Map2k1 protein (UniProt.org). 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 (UniProt.org). 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 (UniProt.org). 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