Mosaic RASopathy Caused by a Somatic HRAS p.Gly12Ser Variant in a Patient With Malignant Melanoma

Area of Science:

• Genetics
• Dermatology
• Oncology

Background:

• Mosaic RASopathies result from postzygotic somatic variants in the Ras/MAPK signaling pathway.
• Clinical manifestations include craniofacial abnormalities, cardiac defects, growth issues, and localized skin problems.
• Diagnostic criteria for these conditions are not clearly established.

Purpose of the Study:

• To present a rare case of mosaic RASopathy caused by a somatic HRAS variant.
• To investigate the genetic basis of the patient's diverse cutaneous manifestations and malignant melanoma.
• To explore the potential association between HRAS-mutant mosaic RASopathy and melanoma.

Main Methods:

• Genetic testing was performed on tissue samples from the patient's skin lesions and peripheral blood.
• An HRAS missense variant (c.34G>A, p.Gly12Ser) was identified in affected tissues but not in blood leukocytes.
• Histopathological examination and analysis of mutant allele proportion in melanoma cells were conducted.

Main Results:

• A somatic HRAS missense variant (p.Gly12Ser) was detected in sebaceous nevus, pigmented skin lesion, palmoplantar keratoderma, and metastatic melanoma.
• No pathogenic HRAS variant was found in peripheral blood leukocytes or normal skin.
• This is the first reported case of mosaic RASopathy co-occurring with malignant melanoma.

Conclusions:

• The patient was diagnosed with HRAS-mutant mosaic RASopathy based on the identified somatic variant and clinical features.
• The co-occurrence of mosaic RASopathy and malignant melanoma warrants further investigation into their potential association.
• The high proportion of mutant alleles in melanoma cells suggests possible loss of heterozygosity, requiring further study.