Mosaic pathogenic HRAS variant in a patient with nevus spilus with agminated Spitz nevi and parametrial-uterine rhabdomyosarcoma

Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort

“…Here we present the data derived from our experience in NGS testing of 358 unique specimens from 343 individuals for DoSM over the course of 5 years. Although discrete aspects from 16 case subjects (4.7%) have been reported previously, [9][10][11] this report is a comprehensive review of the aggregate data across the entire cohort. Our findings stress the importance of several factors unique to testing in the somatic setting: multiplexing with broad exonic sequence coverage of multiple gene targets, high unique coverage depth, and directed selection of specimens from diseaseaffected tissue.…”

What do mosaic RASopathies tell us about carcinogenesis?

“…Thus, it has not been a surprise that deep genomic sequencing techniques have demonstrated somatic mutations that are limited to the affected tissue and not present in the germline of affected individuals. What is noteworthy, however, is that virtually all of these genes have been previously associated with a wide variety of human cancers . Specifically, in genes that govern cell proliferation, cell‐cycle progression and apoptosis.…”

“…With mosaic mutations, the earlier the mutation, the more likely multiple tissues will be involved. Although rare, an increasing number of mosaic RASopathies have been associated with solid tumours . This issue of the BJD includes a case of mosaic HRAS mutation in a patient with phacomatosis pigmentokeratotica who developed a rhabdomyosarcoma .…”

“…What is noteworthy, however, is that virtually all of these genes have been previously associated with a wide variety of human cancers. [6][7][8] Specifically, in genes that govern cell proliferation, cell-cycle progression and apoptosis. Retrospectively, this is intuitive as postzygotic somatic mutations that do not offer advantages to cell survival may not persist through development.…”

“…Although rare, an increasing number of mosaic RASopathies have been associated with solid tumours. [6][7][8] This issue of the BJD includes a case of mosaic HRAS mutation in a patient with phacomatosis pigmentokeratotica who developed a rhabdomyosarcoma. 7 This highlights the spectrum of disorders caused by variants in RAS oncogenes, causing developmental syndromes in some cases and cancer in others.…”