| Title: |
Targeted next-generation sequencing for detection of PIK3CA mutations in archival tissues from patients with Klippel–Trenaunay syndrome in an Asian population |
| Authors: |
Yuki Sasaki, Kosuke Ishikawa, Kanako C. Hatanaka, Yumiko Oyamada, Yusuke Sakuhara, Tadashi Shimizu, Tatsuro Saito, Naoki Murao, Tomohiro Onodera, Takahiro Miura, Taku Maeda, Emi Funayama, Yutaka Hatanaka, Yuhei Yamamoto, Satoru Sasaki |
| Source: |
Orphanet Journal of Rare Diseases, Vol 18, Iss 1, Pp 1-12 (2023) |
| Publisher Information: |
BMC, 2023. |
| Publication Year: |
2023 |
| Collection: |
LCC:Medicine |
| Subject Terms: |
Capillary malformations, High-throughput nucleotide sequencing, Klippel–Trenaunay Syndrome, Limb hypertrophy, Lymphatic abnormalities, Phosphatidylinositol 3-Kinase, Medicine |
| More Details: |
Abstract Background Klippel–Trenaunay syndrome (KTS) is a rare slow-flow combined vascular malformation with limb hypertrophy. KTS is thought to lie on the PIK3CA-related overgrowth spectrum, but reports are limited. PIK3CA encodes p110α, a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) that plays an essential role in the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway. We aimed to demonstrate the clinical utility of targeted next-generation sequencing (NGS) in identifying PIK3CA mosaicism in archival formalin-fixed paraffin-embedded (FFPE) tissues from patients with KTS. Results Participants were 9 female and 5 male patients with KTS diagnosed as capillaro-venous malformation (CVM) or capillaro-lymphatico-venous malformation (CLVM). Median age at resection was 14 years (range, 5–57 years). Median archival period before DNA extraction from FFPE tissues was 5.4 years (range, 3–7 years). NGS-based sequencing of PIK3CA achieved an amplicon mean coverage of 119,000x. PIK3CA missense mutations were found in 12 of 14 patients (85.7%; 6/8 CVM and 6/6 CLVM), with 8 patients showing the hotspot variants E542K, E545K, H1047R, and H1047L. The non-hotspot PIK3CA variants C420R, Q546K, and Q546R were identified in 4 patients. Overall, the mean variant allele frequency for identified PIK3CA variants was 6.9% (range, 1.6–17.4%). All patients with geographic capillary malformation, histopathological lymphatic malformation or macrodactyly of the foot had PIK3CA variants. No genotype–phenotype association between hotspot and non-hotspot PIK3CA variants was found. Histologically, the vessels and adipose tissues of the lesions showed phosphorylation of the proteins in the PI3K/AKT/mTOR signaling pathway, including p-AKT, p-mTOR, and p-4EBP1. Conclusions The PI3K/AKT/mTOR pathway in mesenchymal tissues was activated in patients with KTS. Amplicon-based targeted NGS could identify low-level mosaicism from low-input DNA extracted from FFPE tissues, potentially providing a diagnostic option for personalized medicine with inhibitors of the PI3K/AKT/mTOR signaling pathway. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1750-1172 |
| Relation: |
https://doaj.org/toc/1750-1172 |
| DOI: |
10.1186/s13023-023-02893-1 |
| Access URL: |
https://doaj.org/article/b88c018bb5c14062bd0c85b60103e7c1 |
| Accession Number: |
edsdoj.b88c018bb5c14062bd0c85b60103e7c1 |
| Database: |
Directory of Open Access Journals |
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