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- Title
Targeted next-generation sequencing for detection of PIK3CA mutations in archival tissues from patients with Klippel–Trenaunay syndrome in an Asian population: List the full names and institutional addresses for all authors.
- Authors
Sasaki, Yuki; Ishikawa, Kosuke; Hatanaka, Kanako C.; Oyamada, Yumiko; Sakuhara, Yusuke; Shimizu, Tadashi; Saito, Tatsuro; Murao, Naoki; Onodera, Tomohiro; Miura, Takahiro; Maeda, Taku; Funayama, Emi; Hatanaka, Yutaka; Yamamoto, Yuhei; Sasaki, Satoru
- 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.
- Subjects
NUCLEOTIDE sequencing; ASIANS; LYMPHATIC abnormalities; PHOSPHATIDYLINOSITOL 3-kinases; FOOT; MISSENSE mutation; ADIPOSE tissues
- Publication
Orphanet Journal of Rare Diseases, 2023, Vol 18, Issue 1, p1
- ISSN
1750-1172
- Publication type
Article
- DOI
10.1186/s13023-023-02893-1