Functional characterization of all CDKN2A missense variants and comparison to in silico models of pathogenicity

  1. Department of Pathology, the Johns Hopkins University School of Medicine; Baltimore, 21287, USA
  2. Division of Integrated Genomics, Translational Genomics Research Institute; Phoenix, 85004, USA
  3. Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope; Duarte, 91010, USA
  4. Department of Oncology, the Johns Hopkins University School of Medicine; Baltimore, 21287, USA

Peer review process

Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, and public reviews.

Read more about eLife’s peer review process.

Editors

  • Reviewing Editor
    Murim Choi
    Seoul National University, Seoul, Korea, the Republic of
  • Senior Editor
    Murim Choi
    Seoul National University, Seoul, Korea, the Republic of

Reviewer #1 (Public Review):

Summary:
Kimura et al performed a saturation mutagenesis study of CDKN2A to assess the functionality of all possible missense variants and compare them to previously identified pathogenic variants. They also compared their assay result with those from in silico predictors.

Strengths:
CDKN2A is an important gene that modulates cell cycle and apoptosis, therefore it is critical to accurately assess the functionality of missense variants. Overall, the paper reads well and touches upon major discoveries in a logical manner.

Weaknesses:
The paper lacks proper details for experiments and basic data, leaving the results less convincing. Analyses are superficial and do not provide variant-level resolution.

Reviewer #2 (Public Review):

This study describes a deep mutational scan across CDKN2A using suppression of cell proliferation in pancreatic adenocarcinoma cells as a readout for CDKN2A function. The results are also compared to in silico variant predictors currently utilized by the current diagnostic frameworks to gauge these predictors' performance. The authors also functionally classify CDKN2A somatic mutations in cancers across different tissues.

This study is a potentially important contribution to the field of cancer variant interpretation for CDKN2A, but is almost impossible to review because of the severe lack of details regarding the methods and incompleteness of the data provided with the paper. We do believe that the cell proliferation suppression assay is robust and works, but when it comes to the screening of the library of CDKN2A variants the lack of primary data and experimental detail prevents assessment of the scientific merit and experimental rigor.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation