Mosaicism for oncogenic G12D KRAS mutation associated with epidermal nevus, polycystic kidneys and rhabdomyosarcoma

Abstract

This report shows for the first time that a KRAS mutation in epiderma causes EN. Observation of the same G12D KRAS mutation in two distinct regions of the body strongly suggests a somatic mosaicism. Finally, this report highlights the potentially underestimated importance of mosaic oncogene mutations in childhood cancers.

Keratinocytic epidermal nevi are associated with mosaicRASmutations

“…Interestingly, the HRAS p.G13R mutation occurs in tumours as well as in KEN, but it has not been described in the germline of CS patients, suggesting that although it is tolerated in the mosaic state, it may be lethal in the germline. The KRAS p.G12D mutation—the most frequent somatic KRAS substitution found in cancer—has been described in the mosaic state in a 6-month-old infant with a KEN and a rhabdomyosarcoma18 and is reported here in one KEN. This amino acid substitution has not been described in the germline, in agreement with the fact that its constitutive expression in the mouse is embryonic lethal 19.…”

“…Because the term ‘RASopathy’ is defined by syndromes resulting from germline mutations, we suggest the term ‘mosaic RASopathy’ to describe KEN and KEN syndrome18 23 as well as some rare cases of mosaic CS 17. Additional syndromes may be added to this list in the future because the genetic basis of many mosaic disorders remains unknown.…”

Acanthosis nigricans nævoïde ou « RAVEN » (rounded and velvety epidermal nevus) : trois cas

“…Il est donc tentant de postuler que le RAVEN pourrait être lié à un mosaïcisme post-zygotique sur une mutation du gène FGFR3 présente dans des acanthosis nigricans et peutêtre distincte de la mutation du codon 248 qui prédomine dans les formes habituelles d'hamartome épidermique. Il faut cependant rappeler que d'autres gènes de la même voie de signalisation cellulaire ont été impliqués dans des naevus épidermiques ou des kératoses séborrhéiques [16,17].…”

Mosaic RASopathies

“…Of the two reported patients with an epidermal nevus syndrome caused by a RAS mutation, one patient developed a rhabdomyosarcoma in childhood. 18 A postzygotic KRAS G12D mutation was identified as the underlying mutation, suggesting that mosaicism of this genetic alteration caused the keratinocytic epidermal nevus and contributed to the rhabdomyosarcoma. This assumption is compatible with the reported dysregulation of the RAS signaling pathway in human rhabdomyosarcoma.…”

“…Neurofibromatosis type I is caused by germline mutations of the NF1 gene, which encodes instance, the co-occurrence of a keratinocytic epidermal nevus, a rhabdomyosarcoma, polycystic kidneys and growth retardation in an infant could be attributed to an oncogenic mosaic KRAS G12D mutation. 18 In a second patient with a systematized keratinocytic epidermal nevus, who had developed multiple urothelial carcinomas, a mosaic HRAS G12S mutation was identified in the keratinocytic epidermal nevus, the urothelium, the urothelial cell carcinomas and in the blood leukocytes. 19 Both patient cases are examples of mosaic RASopathies.…”