A mosaic variant in
            <i>
              <scp>MAP</scp>
              2K1
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            is associated with giant naevus spilus‐type congenital melanocytic naevus and melanoma development

Muthiah, Siobhan; Polubothu, Satyamaanasa; Husain, Akhtar; Oliphant, T.; Kinsler, Veronica A.; Rajan, Neil

doi:10.1111/bjd.19118

Cited by 7 publications

(8 citation statements)

References 6 publications

(19 reference statements)

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“…Nevus spilus-type CMN is featured by large café-au-lait lesion with CMN above, while there is no EN or NS lesion. Until now, nevus spilus-type CMN has been reported to be caused by NRAS and MAP2K1 mutation, 13 whereas in our proband no pathogenic mutation was found in these two genes by NGS. Thus, the diagnosis of nevus spilus-type CMN is excluded in our case.…”

Section: Discussioncontrasting

confidence: 60%

The first case of Chinese phacomatosis pigmentokeratotica diagnosed by a missense HRAS mosaicism

Huang

Zhang

Chen

et al. 2022

The Journal of Dermatology

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Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus (EN) syndrome, featured by co‐occurrence of speckled lentiginous nevus (SLN) and nevus sebaceous (NS). The underlying mechanism has not been clarified. Pathogenic mutations in HRAS, KRAS and BRAF gene are recently recognized as the genetic cause of PPK. Here we present a case of Chinese PPK with a mosaic mutation in HRAS gene. Physical examination of the 4‐year‐old male proband showed NS locating on the scalp, with EN and SLN on trunk and extremities. Except congenital fundus vascular tortuosity, no evidence of extracutaneous abnormalities was found in this case. A rare heterozygous missense c. 181 C>A mosaic mutation in HRAS was identified in samples from NS, EN and pigmented nevus using next‐generation sequencing and Sanger sequencing. Meanwhile, no mutation was found in the non‐lesion skin, hair follicle, or blood DNA. Recent breakthrough in clinical manifestation, genetic mutation and prognosis of PPK is also reviewed.

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Section: Discussioncontrasting

confidence: 60%

The first case of Chinese phacomatosis pigmentokeratotica diagnosed by a missense HRAS mosaicism

Huang

Zhang

Chen

et al. 2022

The Journal of Dermatology

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“…In recent years, several studies have indicated the potential pathogenicity of MAP2K1 variants in malignancy to melanoma. 8,19 We identified four novel MAP2K1 variants (p.I107fs, p.F209fs, p.Q354H and p.G91_L92insHDQARRLVGDLEHHKPSG) in our cohort with CMN, which occurred at an overall frequency of 4.5% (5 of 110). Moreover, these variants were detected alone or in coincidence with NRAS/KRAS variants, adding evidence to the central role of the Ras/Raf/MAPK signalling pathway in CMN.…”

Section: Discussionmentioning

confidence: 85%

“…The findings of this study expand the knowledge of genotype-phenotype correlations in CMN, potentially facilitating a more accurate and comprehensive classification of CMN in clinical practice. 8,11,17,18 The allele load of NRAS p.Q61R/K could be a predictor of the clinical developing pattern in CMN in colour variation, hypertrichosis, surface rugosity, irregular boundary and asymmetry. Especially for patients with giant CMN who would be considered challenging in surgical excision, comprehensive understanding of genetic alterations may add more information in respect to predicting their clinical outcomes during the early stage.…”

Section: Discussionmentioning

confidence: 99%

“…7 Involvement of variants in other genes such as MAP2K1 and BRAF in CMN and a potential pathogenic potential to malignancy such as melanoma were recently indicated. [8][9][10] The correlations of genetic changes with phenotypic characteristics may be necessary for better understanding of the effect of genotype on clinical outcomes. 11 There have been several genotype-phenotype analyses reported previously, but the results are controversial.…”

Section: Introductionmentioning

confidence: 99%

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NRAS p.Q61R/K allele load is correlated to different phenotypes of congenital melanocytic naevi

Xiong

Dai

Zhang

et al. 2022

Clinical and Experimental Dermatology

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Background. Congenital melanocytic naevi (CMN) are known to be associated with mosaic NRAS or BRAF variants. However, the exact correlations of the allele load of mosaic variants in CMN with phenotypic characteristics have not been determined. Aim. To determine the correlation of variants allele load and different phenotypes of CMN. Methods. A panel of genes in the Ras/Raf/MAPK signalling pathway was selected for sequencing in 110 patients with CMN. Correlations between variant allele load and clinical phenotypes, including anatomical localization, projected adult size of the lesion, satellites, subcutaneous nodules, surface rugosity, colour variation and hypertrichosis, were analysed. Results. In addition to the predominant NRAS p.Q61R/K (61.8%) and BRAF p.V600E variants (10%) in patients, we also detected additional variants of NRAS (p.G13R and p.M72fs), BRAF (p.D22N) and MAP2K1 (p.I107fs, p.F209fs, p.Q354H and p.G91_L92insHDQARRLVGDLEHHKPSG). Furthermore, a higher allele load of NRAS p.Q61R/K was found in the trunk and limbs of CMN. It was also found in CMN with larger size, higher colour variation and more significant hypertrichosis, surface rugosity and asymmetry. Conclusion. We discovered more genetic variants of NRAS, BRAF and MAP2K1 and established a correlation between the allele load of NRAS p.Q61R/K and various phenotypes in CMN. The findings of this study potentially facilitate a more accurate and comprehensive classification of CMN in addition to the phenotypic or pathological characteristics used in clinical practice.

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“…In 2019, Jansen P reported an activating MAP2K1 mutation at an overall frequency of 1% in acral nevi [8]. Later in 2020, Muthiah S et al reported MAP2K1 (c.607G > A, p.E203K) in naevus spilus (NS)-type CMN [14].However, it is still unknown whether MAP2K1 mutations are characteristic of CMN, and how MAP2K1 contributes to the pathogenesis of CMN remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Novel genetic alteration in congenital melanocytic nevus: MAP2K1 germline mutation with BRAF somatic mutation

Zou¹,

Sun²,

Zeng

et al. 2020

Hereditas

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Congenital melanocytic nevus (CMN) represent a benign proliferative skin disease in the epidermis and dermis. CMN are historically known to be associated with activating NRAS or BRAF mutations. Melanoma frequently harbors the BRAF p.Val600Glu mutation, which is also commonly found in benign nevi. A recent study reported mutation of MAP2K1, a downstream effector of the RAS-RAF-MEK pathway, in melanoma with an overall frequency of 8%. Later, in 2019, Jansen P detected one activating MAP2K1 mutation in acral nevi. However, it is unknown whether MAP2K1 mutations are common in CMN, and how MAP2K1 contributes to the pathogenesis of CMN remains to be determined. In this study, we report one patient clinically and histologically diagnosed with CMN, with the MAP2K1 germline mutation and a BRAF p.Val600Glu somatic hit in the lesion. To the best of our knowledge, this is the first report of the coexistence of mutated BRAF and MAP2K1 in CMN, which may suggest that MAP2K1 mutations contribute to the occurrence and development of nevus expanding our knowledge of the genetics of CMN.

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A mosaic variant in MAP 2K1 is associated with giant naevus spilus‐type congenital melanocytic naevus and melanoma development

Cited by 7 publications

References 6 publications

The first case of Chinese phacomatosis pigmentokeratotica diagnosed by a missense HRAS mosaicism

The first case of Chinese phacomatosis pigmentokeratotica diagnosed by a missense HRAS mosaicism

NRAS p.Q61R/K allele load is correlated to different phenotypes of congenital melanocytic naevi

Novel genetic alteration in congenital melanocytic nevus: MAP2K1 germline mutation with BRAF somatic mutation

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