Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial
- University of Arizona Cancer Center, United States
- Division of Hematology/Oncology, Department of Medicine, University of Arizona College of Medicine, United States
- Foundation Medicine, Inc, United States
- Rutgers Cancer Institute of New Jersey, United States
- Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, United States
- University of New Mexico Comprehensive Cancer Center, United States
- Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, United States
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, United States
- Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, United States
- Department of Pathology, University of Kentucky College of Medicine and Markey Cancer Center, United States
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, United States
- Department of Molecular and Cellular Biology, College of Science, University of Arizona, United States
- Vascular Biology Program, Boston Children’s Hospital, United States
- Department of Surgery, Harvard Medical School, United States
- Department of Pathology, Rutgers Robert Wood Johnson Medical School, United States
- Division of Medical Oncology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, United States
- Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, United States
Figures
Figure 1
Mutational landscape and histopathology of lymphatic malformations (LMs).
(A) Oncoprint showing mutational landscape of 30 LM samples sequenced. (B) Lollipop plot showing spectrum of PIK3CA and NRAS mutations in this cohort. (C) Schema showing details of GOPC–ROS1 fusion …
Figure 2
Imaging and histological analysis of lymphatic malformation (LM) patient.
(A) Baseline CT abdomen scan at the time of presentation demonstrating a large retroperitoneal/pancreatic LM. (B) CT abdomen scan 6 weeks after the initiation of alpelisib. (C) CT abdomen scan 1 …
Figure 3
Alpelisib reduces lymphatic malformation-lymphatic endothelial cell (LM-LEC) viability.
(A) Logarithmic dose–response curve of alpelisib was performed using the xCELLigence RTCA system. 1, 3, 10, 30, and 100 nM (n = 5 replicates) of alpelisib were used to determine the …
Figure 4
RNA-seq analysis of lymphatic malformation (LM) samples from index patient (#9).
(A) The heatmap summarizes the results of the differential gene expression analysis. Up- and downregulated genes are shaded red and blue, respectively. (B) The volcano plot summarizes the …
Figure 5
Graphical summary of the mutations found in genomic analysis of lymphatic malformation (LM) patient cohort (created with BioRender.com).
(A) The majority of LMs have driver mutations that are potentially targetable. (B) LMs with NRAS mutations had kaposiform histopathology. (C) An N-of-1 clinical trial is reported in a patient with a …
Tables
Table 1
Clinical and histological features of lymphatic malformation cohort.
| Patient | Age(years) | Sex | Submitted clinical syndrome | Localized vs. multifocal | Location of LM(s) | Specimen type | LM histology | PIK3CA or NRAS alteration | % VAF |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 9 | M | CLOVES | Multifocal | Superficial soft tissues | Excision | Conventional | PIK3CA E542K | 14 |
| 2 | 4 | F | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA E542K | 7 | |
| 3 | 1 | F | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA H1047R | 11 | |
| 4 | 17 | M | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA H1047R | 4 | |
| 5 | 18 | M | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA H1047L | 4 | |
| 6 | 8 | F | Klippel–Trenaunay | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA H1047R | 9 |
| 7 | 9 | M | Localized | Visceral | Core biopsy | Conventional | PIK3CA E545K | 7 | |
| 8 | 3 | F | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA C420R | 5 | |
| 9 | 23 | M | Localized | Visceral | Incisional biopsy | Conventional | PIK3CA H1047R | 4 | |
| 10 | 16 | F | PTEN-like hamartoma | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA H1047R | 3 |
| 11 | 3 | F | CLOVES | Multifocal | Superficial soft tissues | Excision | Conventional | PIK3CA E545K | 12 |
| 12 | 1 | M | Multifocal | Superficial soft tissues | Excision | Conventional | PIK3CA H1047R | 2 | |
| 13 | 4 | F | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA E542K | 6 | |
| 14 | 5 | M | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA H1047R | 5 | |
| 15 | 1 | F | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA E545K | 1 | |
| 16 | 14 | F | Multifocal | Visceral | Excision | Conventional | PIK3CA C420R | 14 | |
| 17 | 2 | F | CLOVES | Multifocal | Superficial soft tissues | Excision | Conventional | PIK3CA C420R | 38 |
| 18 | 16 | F | CLOVES | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA E453K | 32 |
| 19 | 10 | F | CLOVES | Multifocal | Superficial soft tissues | Excision | Conventional | PIK3CA H1047L | 15 |
| 20 | 9 | M | Localized | Superficial soft tissues | Excision | Conventional | PIK3CA H1047R | 5 | |
| 21 | 9 | F | Multifocal | Visceral | Excision | Kaposiform | NRAS Q61R | 5 | |
| 22 | 8 | M | Multifocal | Superficial soft tissues | Excision | Kaposiform | NRAS Q61R | 5 | |
| 23 | 9 | F | Multifocal | Visceral | Excision | Kaposiform | NRAS Q61R | 1 | |
| 24 | 45 | M | Multifocal | Visceral | Core biopsy | Conventional | NRAS Q61R | 6 | |
| 25 | 10 | F | Localized | Superficial soft tissues | Core biopsy | Kaposiform | NRAS Q61R | 14 | |
| 26 | 17 | M | Multifocal | Superficial soft tissues | Excision | Conventional | WT | NA | |
| 27 | 24 | M | Localized | Bone | Core biopsy | Conventional | WT | NA | |
| 28 | 3 | M | Multifocal | Superficial soft tissues | Excision | Conventional | WT | NA | |
| 29 | 11 | F | Localized | Superficial soft tissues | Excision | Conventional | WT | NA | |
| 30 | 9 | F | Localized | Superficial soft tissues, bone | Biopsy | Conventional | WT | NA |
-
CLOVES – congenital lipomatous overgrowth, vascular anomalies, epidermal nevi, and skeletal anomalies; NA – not applicable; VAF – variant allele frequency of PIK3CA or NRAS.
Additional files
-
Supplementary file 1
Somatic coding mutations identified from whole-genome sequencing.
The genetic coding variants that exist in lymphatic malformation (LM) but do not exist in germline DNA. These pass MuTect2 quality filters (designed to call somatic variants only) and have three or more alternate reads. VAF, variant allele frequency; COSMIC, Catalogue Of Somatic Mutations In Cancer.
- https://cdn.elifesciences.org/articles/74510/elife-74510-supp1-v2.docx
-
Transparent reporting form
- https://cdn.elifesciences.org/articles/74510/elife-74510-transrepform1-v2.pdf
