2303P - Protein functional interpretation of gene variants observed in clinical next-generation sequencing (NGS) for pleural mesothelioma

Background

The interpretation of gene variants from NGS data may support clinical and treatment decisions in pleural mesothelioma. Predicting how a variant can affect the functions of the protein- or disease-relevant pathways is challenging and, so far, it largely relies on gene-centric algorithms. We complement this by integrating a protein-centric interpretation of the variants in order to expand the functional information accessible from clinical NGS.

Methods

We have screened for pleural mesothelioma clinical NGS datasets accessible from literature reports focusing on the relevant genes BAP1 and NF2. NGS results are combined with protein information from neXtProt using an in-house developed program. Conservation-based predictions are integrated with structural and functional protein information to assess the functional impact of the variants. The pleural mesothelioma molecular pathway in the WikiPathways knowledgebase permits us to interpret the relevance of the variant within its pathway environment (https://www.wikipathways.org/pathways/WP5087.html).

Results

The variants from an initial NGS dataset have been mapped on the protein sequences, resulting in 209 protein variants for BAP1 and 181 for NF2 isoform 1. Functional predictions from the algorithms SIFT and PolyPhen-2 embedded in neXtProt presented approx. 60% agreement for BAP1 and 51% for NF2. 13% of the BAP1 and 22% of the NF2 variants had no prediction. The integration of the protein-centric information refined the functional interpretation of 121 variants in BAP1 and 107 in NF2 located in regions critical for the function of the proteins, like interacting or enzymatically active domains, FERM domains or loci of post-translational modifications. Among them, 67 variants with missing or ambiguous prediction between SIFT and PolyPhen-2 (30 in BAP1, 37 in NF2). The molecular pathways of pleural mesothelioma revealed critical sites in the BAP1 and NF2 pathways potentially affected by the variants (WikiPathways:WP5087; Malignant pleural mesothelioma (WP5087)).

Conclusions

Protein-centric and pathway-embedded interpretation of gene variants may complement NGS information for clinical decisions in pleural mesothelioma.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

The Marlies Schwegler Foundation.

Disclosure

F.W.F. Cerciello: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, PharmaMar. All other authors have declared no conflicts of interest.