Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial

  1. Montaser F Shaheen  Is a corresponding author
  2. Julie Y Tse
  3. Ethan S Sokol
  4. Margaret Masterson
  5. Pranshu Bansal
  6. Ian Rabinowitz
  7. Christy A Tarleton
  8. Andrey S Dobroff
  9. Tracey L Smith
  10. Thèrése J Bocklage
  11. Brian K Mannakee
  12. Ryan N Gutenkunst
  13. Joyce Bischoff
  14. Scott A Ness
  15. Gregory M Riedlinger
  16. Roman Groisberg
  17. Renata Pasqualini
  18. Shridar Ganesan
  19. Wadih Arap  Is a corresponding author
  1. University of Arizona Cancer Center, United States
  2. Division of Hematology/Oncology, Department of Medicine, University of Arizona College of Medicine, United States
  3. Foundation Medicine, Inc, United States
  4. Rutgers Cancer Institute of New Jersey, United States
  5. Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, United States
  6. University of New Mexico Comprehensive Cancer Center, United States
  7. Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, United States
  8. Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, United States
  9. Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, United States
  10. Department of Pathology, University of Kentucky College of Medicine and Markey Cancer Center, United States
  11. Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, United States
  12. Department of Molecular and Cellular Biology, College of Science, University of Arizona, United States
  13. Vascular Biology Program, Boston Children’s Hospital, United States
  14. Department of Surgery, Harvard Medical School, United States
  15. Department of Pathology, Rutgers Robert Wood Johnson Medical School, United States
  16. Division of Medical Oncology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, United States
  17. Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, United States

Peer review process

This article was accepted for publication as part of eLife's original publishing model.

History

  1. Version of Record updated
  2. Version of Record published
  3. Accepted
  4. Preprint posted
  5. Received

Decision letter

  1. Mone Zaidi
    Senior and Reviewing Editor; Icahn School of Medicine at Mount Sinai, United States
  2. Friedrich Kapp
    Reviewer

Our editorial process produces two outputs: i) public reviews designed to be posted alongside the preprint for the benefit of readers; ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.

Decision letter after peer review:

Thank you for submitting your article "Genomic Landscape of Lymphatic Malformations: A Case Series and Response to the PI3Kα Inhibitor Alpelisib in an N-of-One Clinical Trial" for consideration by eLife. Your article has been reviewed by 2 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Martin Pollak as the Senior Editor. The following individual involved in the review of your submission has agreed to reveal their identity: Friedrich Kapp (Reviewer #1).

Below, I have provided a summary of essential revisions. Please provide a point-by-point rebuttal, also taking into account comments made under the heading 'Public Review', as appropriate changes in response would strengthen the manuscript further.

Essential revisions:

1. Please provide a more accurate description and naming of vascular malformations, as well as distinguish these from tumors.

2. The abstract would be improved if it included more specific aspects of the results, e.g. the number of patients with PIK3CA and NRAS mutations and what they mean by "complete response" and "sensitive" to alpelisib.

3. The CT scan images should indicate the LM with arrows.

https://doi.org/10.7554/eLife.74510.sa1

Author response

Essential revisions:

1. Please provide a more accurate description and naming of vascular malformations, as well as distinguish these from tumors.

Thank you for the suggestion to clarify the nomenclature used in this manuscript for the non-expert reader. We considered the diagnosis and classification of vascular anomalies (vascular malformations and others) to be a holistic integration of clinical examination, imaging studies, pathology diagnosis, and/or genomic results. One of the limitations of our study is that the CGP cohort was a study of data available from an international reference laboratory. While the use of data from a reference laboratory enables the study of relatively high numbers of rare diseases, it limits us to only clinical information provided by the ordering physicians at the time of testing and only to one representative pathology specimen submitted by the pathology laboratory. Therefore, the scope of our study did not enable outreach to ordering physicians and pathologists to determine if and how the genomic results refined the working clinical diagnosis and/or pathologic diagnoses.

Recognizing these inherent limitations, we agreed to use the term lymphatic malformations to describe the lesions in our cohort. Lymphatic malformation is widely accepted to include a clinicopathologic continuum of benign tumors of lymphatic origin (https://rarediseases.org/rare-diseases/lymphatic-malformations/), including cystic lymphangioma, kaposiform lymphangiomatosis, macro/microcystic lymphatic malformation. While evidently imperfect, we have now clarified their use of this term in the Introduction.

2. The abstract would be improved if it included more specific aspects of the results, e.g. the number of patients with PIK3CA and NRAS mutations and what they mean by "complete response" and "sensitive" to alpelisib.

Thank you for the suggestion. We have specified the number of patients in the CGP cohort with PIK3CA and NRAS mutations in the Abstract. We have also clarified the language “complete response” and “sensitive” to treatment.

3. The CT scan images should indicate the LM with arrows.

We have now indicated the LM in the CT images to allow easier visualization for the readers.

https://doi.org/10.7554/eLife.74510.sa2

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  1. Montaser F Shaheen
  2. Julie Y Tse
  3. Ethan S Sokol
  4. Margaret Masterson
  5. Pranshu Bansal
  6. Ian Rabinowitz
  7. Christy A Tarleton
  8. Andrey S Dobroff
  9. Tracey L Smith
  10. Thèrése J Bocklage
  11. Brian K Mannakee
  12. Ryan N Gutenkunst
  13. Joyce Bischoff
  14. Scott A Ness
  15. Gregory M Riedlinger
  16. Roman Groisberg
  17. Renata Pasqualini
  18. Shridar Ganesan
  19. Wadih Arap
(2022)
Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial
eLife 11:e74510.
https://doi.org/10.7554/eLife.74510

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https://doi.org/10.7554/eLife.74510