25. Genetic spectrum of RAS Alterations-A Highlight of in-frame insertion variants in association with vascular anomalies

Abstract

Listen

Translate article

RAS genes constitute a multigene family that includes HRAS, NRAS, and KRAS. Activated variants in RAS genes, occurring at hotspots including Gly12, Gly13, and Gln61, have been found in a wide variety of tumor types. Those hotspots have also been described in disorders of somatic mosaicism (DoSM), including vascular tumors, vascular malformations, nevus syndrome, segmental overgrowth, and digital anomalies. Here, we review a cohort of 938 individuals with DoSM and identified 64 cases with pathogenic (P) and likely pathogenic (LP) variants in the RAS genes, including 37 cases in the KRAS gene, 18 in the HRAS gene, and 9 in the NRAS gene. Unlike the recurrent hotspots, 10 of the 64 cases (15.6%) carried an in-frame insertion P/LP variant in either KRAS (n=4) or HRAS (n=6). In-frame insertion variants in HRAS and KRAS have not been observed in cancer databases. Only a few similar KRAS in-frame insertions in tumor samples have been previously published. Functional studies have shown that in-frame RAS insertions in the switch II region weakly increase RAS signaling via a decrease in intrinsic GTPase activity. Germline, in-frame insertion HRAS variants have been observed in Costello syndrome patients with milder phenotypes. Comparably, individuals with in-frame insertion HRAS and KRAS variants in this study had milder phenotypes compared to those with missense RAS variants. This study has reviewed the genetic spectrum of RAS gene alterations in a large cohort of cases with DoSM, highlighting the unique group of in-frame insertion variants in association with vascular malformation.