Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases
Publication year
2019Source
Genes, Chromosomes & Cancer, 58, 8, (2019), pp. 541-550ISSN
Publication type
Article / Letter to editor
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Organization
Pathology
Dermatology
Human Genetics
Surgery
Medical Imaging
Journal title
Genes, Chromosomes & Cancer
Volume
vol. 58
Issue
iss. 8
Page start
p. 541
Page end
p. 550
Subject
Radboudumc 10: Reconstructive and regenerative medicine RIHS: Radboud Institute for Health Sciences; Radboudumc 14: Tumours of the digestive tract RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences; Radboudumc 17: Women's cancers RIHS: Radboud Institute for Health Sciences; Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life SciencesAbstract
Vascular malformations are part of overgrowth syndromes characterized by somatic mosaic mutations or rarely by germline mutations. Due to their similarities and diversity, clinicopathological classification can be challenging. A comprehensive targeted Next Generation Sequencing screen using Unique Molecular Identifiers with a technical sensitivity of 1% mutant alleles was performed for frequently mutated positions in >/=21 genes on 319 formalin-fixed paraffin-embedded samples. In 132 out of 319 cases pathogenic mosaic mutations were detected affecting genes previously linked to vascular malformations e.g. PIK3CA (n=80), TEK (TIE2) (n=11), AKT1 (n=1), GNAQ (n=7), GNA11 (n=4), IDH1 (n=3), KRAS (n=9), and NRAS (n=1). Six cases harbored a combination of mutations in PIK3CA and in GNA11 (n=2), GNAQ (n=2), or IDH1 (n=2). Aberrations in PTEN and RASA1 with a variant allele frequency approaching 50% suggestive of germline origin were identified in six out of 102 cases tested; four contained a potential second hit at a lower allele frequency. Ninety-one of the total 142 pathogenic mutations were present at a variant allele frequency <10% illustrating the importance of sensitive molecular analysis. Clinicopathological characteristics showed a broad spectrum and overlap when correlated with molecular data. Sensitive screening of recurrently mutated genes in vascular malformations may help to confirm the diagnosis and reveals potential therapeutic options with a significant contribution of PIK3CA/mTOR and RAS-MAPK pathway mutations. The co-existence of two activating pathogenic mutations in parallel pathways illustrates potential treatment challenges and underlines the importance of multigene testing. Detected germline mutations have major clinical impact.
This item appears in the following Collection(s)
- Academic publications [238441]
- Electronic publications [122508]
- Faculty of Medical Sciences [90373]
- Open Access publications [97504]
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