Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations

Zenner, Kaitlyn; Cheng, Chi Vicky; Jensen, Dana M.; Timms, Andrew E.; Shivaram, Giridhar M.; Bly, Randall A.; Ganti, Sheila; Whitlock, Kathryn B.; Dobyns, William B.; Perkins, Jonathan A.; Bennett, James T.

doi:10.1172/jci.insight.129884

Cited by 45 publications

(73 citation statements)

References 49 publications

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“…Only a small fraction of cells in the LM possess the variant and there is significant intralesional heterogeneity, therefore multiple lesion samples may be required to establish a molecular diagnosis. 11 Given our prior results suggesting a single LM sample may be insufficient for variant detection, we did not expect every cyst fluid sample to be variant positive. Interestingly, the cfDNA compartment was distinct from the pelleted material from which gDNA was extracted.…”

Section: Discussionmentioning

confidence: 99%

“…PCR was performed as previously described. 11 All samples were run in quadruplicate with a maximum of 25 ng DNA per well or maximum volume 11 μL if cfDNA concentration was low. Each run included a no template control, wild-type (WT) gDNA control, WT cfDNA control, and variant gDNA control.…”

Section: Methodsmentioning

confidence: 99%

“…Although familial disorders exist, most VM are sporadic with the majority caused by post-zygotic, activating pathogenic variants in oncogenes within the PI3K-MTOR and RAS-MAPK pathways. 9 Previous studies have shown clear genotype-phenotype demarcations: LM are associated with PIK3CA variants, 10 , 11 VeM with TEK and PIK3CA variants, 12 , 13 and AVM with MAP2K1, BRAF, and KRAS variants. 14 – 16 These variants are restricted to a small fraction (1–20%) of cells within VM tissue and are generally not detected in DNA isolated from blood-cells or surrounding normal tissues (e.g.…”

Section: Introductionmentioning

confidence: 94%

“…skin biopsies overlying the lesion). 11 Consequently, molecular diagnosis currently requires surgically excised VM tissue. VM resection requires specialized surgical expertise, and associated risks include bleeding, infection, chyle leak, nerve injury, and poor wound healing.…”

Section: Introductionmentioning

confidence: 99%

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Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations

Zenner

Jensen

Cook

et al. 2021

Genetics in Medicine

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Purpose: Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery. We hypothesized that cell-free DNA (cfDNA) could provide molecular diagnoses for patients with isolated VM. Methods: cfDNA was isolated from plasma or cyst fluid from patients with arteriovenous malformations (AVM), venous malformations (VeM), or lymphatic malformations (LM), and assayed for known pathogenic variants using droplet digital PCR (ddPCR). Cyst fluid cfDNA from an independent cohort of LM patients was prospectively screened for variants using a multiplex ddPCR assay. Results: Variants were detected in plasma cfDNA in patients with AVM (2/8) and VeM (1/3). Variants were detected in cyst fluid cfDNA (7/7) but not plasma (0/26) in LM patients. Prospective testing of cyst fluid cfDNA with multiplex ddPCR identified variants in LM patients who had never undergone surgery (4/5). Conclusion: Variants were detected in plasma from AVM and VeM patients, and in cyst fluid from patients with LM. These data support investigation of cfDNA-based molecular diagnostics for VM patients which may provide opportunities to initiate targeted pharmacotherapies without prior surgery.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations

Zenner

Jensen

Cook

et al. 2021

Genetics in Medicine

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“…Our patient's p.Val344Met mutation is not one of three PIK3CA hotspot mutations (p.His1047Arg, p.Glu545Lys, and p.Glu542Lys) present at high frequency (14%‐38%) in the COSMIC database. In fact, this non‐hotspot p.Val344Met mutation represents 0.2% of PIK3CA mutations in COSMIC and suggests that it is only weakly activating, consistent with the milder PROS spectrum disease seen in our patient. We speculate puberty may have stimulated proliferation of this acquired CM.…”

Section: Discussionmentioning

confidence: 99%

A PIK3CA mutation in an acquired capillary malformation

Rosenthal

Sibbald

Jen

et al. 2019

Pediatric Dermatology

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Acquired capillary malformations are rare vascular anomalies composed of dilated capillaries in the skin. We present a pediatric case of an acquired capillary malformation as a novel presentation of the PIK3CA-related overgrowth syndromes. Using next-generation sequencing, we identified a PIK3CA p.Val344Met mutation within the acquired capillary malformation with possible prognostic and therapeutic significance.

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Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA

Nriagu,

Williams,

Brewer

et al. 2023

American J of Med Genetics Pt A

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Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co‐occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA—a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co‐occur in individuals with Turner syndrome.

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Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations

Cited by 45 publications

References 49 publications

Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations

Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations

A PIK3CA mutation in an acquired capillary malformation

Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA

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