Abstract 2303P
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.
Resources from the same session
2294P - Whole genome sequencing to define the germline-somatic interaction in young-onset lung cancer
Presenter: Jaclyn LoPiccolo
Session: Poster session 08
2295P - Pan-cancer prevalence of MET fusions and clinical response to MET- targeted therapy
Presenter: Morana Vojnic
Session: Poster session 08
2296P - SGLT2 i dapagliflozin reduces NF-kB expression in heart and kidneys of preclinical models exposed to doxorubicin through MYd-88 and NLRP3 pathways
Presenter: Nicola Maurea
Session: Poster session 08
2297P - Gene co-expression networks capture the potential pathogenesis and progression of upper tract urothelial cancer
Presenter: Tingting Fu
Session: Poster session 08
2298P - Feasibility of ex vivo drug sensitivity testing in urothelial cancer: EVITA trial
Presenter: Mathijs Scholtes
Session: Poster session 08
2299P - Mebendazole enhances the anticancer effect of irinotecan and check-point inhibitor in vitro and in vivo
Presenter: Sharmineh Mansoori
Session: Poster session 08
2300P - Clonal hematopoiesis of indeterminate potential (CHIP) in patients with advanced NSCLC treated with immune checkpoint blockers (ICB) as monotherapy: Analysis of the PREMIS study
Presenter: Julieta Rodriguez
Session: Poster session 08
2301P - Combining cancer patient spatial transcriptomics and bulk RNA-Seq data to drive insights into NSCLC
Presenter: Julia Bischof
Session: Poster session 08
2302P - Efficacy assessment of targeted and immunotherapies for personalised treatment of melanoma using 2D and 3D ex-vivo assays
Presenter: Md Marufur Rahman
Session: Poster session 08
2304P - A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19 -17)
Presenter: Eun Joo Kang
Session: Poster session 08