Non-hotspot PIK3CA mutations are more frequent in CLOVES than in common or combined lymphatic malformations

Orphanet Journal of Rare Diseases

Anne Dompmartin¹  Catheline Vilain²  Annamaria Weitz-Tuoretmaa³  Jussi Laranne⁴  Angela Queisser⁵  Nassim Homayun Sepehr⁵  Raphaël Helaers⁵  Matthieu J. Schlögel⁵  Elodie Fastré⁵  Pascal Brouillard⁵  Simon Boutry⁵  Laurence M. Boon⁶  Miikka Vikkula⁷  Sandra Schmitz⁸  Philippe Clapuyt⁸  Frank Hammer⁸  Louise Pasquesoone⁹ 

[1] Department of Dermatology, Université de Caen Basse Normandie, CHU Caen, Caen, France;Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium;Department of Otolaryngology, Kokkola Central Hospital, Kokkola, Finland;Department of Otorhinolaryngology, Head and Neck Surgery, Tampere University Hospital, Tampere, Finland;Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74 (+5), bte B1.74.06, 1200, Brussels, Belgium;Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74 (+5), bte B1.74.06, 1200, Brussels, Belgium;Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium;VASCERN VASCA European Reference Centre, Brussels, Belgium;Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74 (+5), bte B1.74.06, 1200, Brussels, Belgium;Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium;VASCERN VASCA European Reference Centre, Brussels, Belgium;Walloon Excellence in Lifesciences and Biotechnology (WELBIO), University of Louvain, Brussels, Belgium;Otolaryngology Department, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium;Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium;VASCERN VASCA European Reference Centre, Brussels, Belgium;Service de Chirurgie Plastique Reconstructive, Hôpital Salengro, CHU de Lille, Lille, France;

关键词: Lymphatic malformation;    Isolated;    Gene;    Mutation;    Somatic;    PI3K;    Epidemiology;    Theragnostic;    Allele;    Frequency;   

DOI  :  10.1186/s13023-021-01898-y

来源: Springer

【 摘 要 】

BackgroundTheragnostic management, treatment according to precise pathological molecular targets, requests to unravel patients’ genotypes. We used targeted next-generation sequencing (NGS) or digital droplet polymerase chain reaction (ddPCR) to screen for somatic PIK3CA mutations on DNA extracted from resected lesional tissue or lymphatic endothelial cells (LECs) isolated from lesions. Our cohort (n = 143) was composed of unrelated patients suffering from a common lymphatic malformation (LM), a combined lymphatic malformation [lymphatico-venous malformation (LVM), capillaro-lymphatic malformation (CLM), capillaro-lymphatico-venous malformation (CLVM)], or a syndrome [CLVM with hypertrophy (Klippel-Trenaunay-Weber syndrome, KTS), congenital lipomatous overgrowth-vascular malformations-epidermal nevi -syndrome (CLOVES), unclassified PIK3CA-related overgrowth syndrome (PROS) or unclassified vascular (lymphatic) anomaly syndrome (UVA)].ResultsWe identified a somatic PIK3CA mutation in resected lesions of 108 out of 143 patients (75.5%). The frequency of the variant allele ranged from 0.54 to 25.33% in tissues, and up to 47% in isolated endothelial cells. We detected a statistically significant difference in the distribution of mutations between patients with common and combined LM compared to the syndromes, but not with KTS. Moreover, the variant allele frequency was higher in the syndromes.ConclusionsMost patients with an common or combined lymphatic malformation with or without overgrowth harbour a somatic PIK3CA mutation. However, in about a quarter of patients, no such mutation was detected, suggesting the existence of (an)other cause(s). We detected a hotspot mutation more frequently in common and combined LMs compared to syndromic cases (CLOVES and PROS). Diagnostic genotyping should thus not be limited to PIK3CA hotspot mutations. Moreover, the higher mutant allele frequency in syndromes suggests a wider distribution in patients’ tissues, facilitating detection. Clinical trials have demonstrated efficacy of Sirolimus and Alpelisib in treating patients with an LM or PROS. Genotyping might lead to an increase in efficacy, as treatments could be more targeted, and responses could vary depending on presence and type of PIK3CA-mutation.

【 授权许可】

CC BY