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EGFR Pathway-Based Gene Signatures of Druggable Gene Mutations in Melanoma, Breast, Lung, and Thyroid Cancers

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Abstract

EGFR, BRAF, PIK3CA, and KRAS genes play major roles in EGFR pathway, and accommodate activating mutations that predict response to many targeted therapeutics. However, connections between these mutations and EGFR pathway expression patterns remain unexplored. Here, we investigated transcriptomic associations with these activating mutations in three ways. First, we compared expressions of these genes in the mutant and wild type tumors, respectively, using RNA sequencing profiles from The Cancer Genome Atlas project database (n = 3660). Second, mutations were associated with the activation level of EGFR pathway. Third, they were associated with the gene signatures of differentially expressed genes from these pathways between the mutant and wild type tumors. We found that the upregulated EGFR pathway was linked with mutations in the BRAF (thyroid cancer, melanoma) and PIK3CA (breast cancer) genes. Gene signatures were associated with BRAF (thyroid cancer, melanoma), EGFR (squamous cell lung cancer), KRAS (colorectal cancer), and PIK3CA (breast cancer) mutations. However, only for the BRAF gene signature in the thyroid cancer we observed strong biomarker diagnostic capacity with AUC > 0.7 (0.809). Next, we validated this signature on the independent literature-based dataset (n = 127, fresh-frozen tissue samples, AUC 0.912), and on the experimental dataset (n = 42, formalin fixed, paraffin embedded tissue samples, AUC 0.822). Our results suggest that the RNA sequencing profiles can be used for robust identification of the replacement of Valine at position 600 with Glutamic acid in the BRAF gene in the papillary subtype of thyroid cancer, and evidence that the specific gene expression levels could provide information about the driver carcinogenic mutations.

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Data Availability

Transcriptomic data used for experimental validation of gene signatures were deposited to the Gene Expression Omnibus database (GEO) under accession no. GSE138042. Raw FASTQ data are available in the SRA archive under accession no. PRJNA588725. Description of the clinically relevant (age, sex, diagnosis, tumor histotype, BRAFV600E mutation status) and technical (RIN, date of sequencing) information is given in the Table S1 in the Supplement.

Abbreviations

BC:

breast cancer

CRC:

colorectal cancer

LA:

lung adenocarcinoma

TC:

thyroid cancer

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Funding

This study was financially supported by the Russian Science Foundation (project no. 18-15-00061).

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Correspondence to Anton Buzdin.

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he authors Mikhail Raevskiy, Andrew Garazha, and Anton Buzdin are employed by the company OmicsWay Corp., and Maxim Sorokin is employed by the company Oncobox Ltd. The remaining authors had only academic affiliations. All the authors declare no conflicts of interest. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Raevskiy, M., Sorokin, M., Vladimirova, U. et al. EGFR Pathway-Based Gene Signatures of Druggable Gene Mutations in Melanoma, Breast, Lung, and Thyroid Cancers. Biochemistry Moscow 86, 1477–1488 (2021). https://doi.org/10.1134/S0006297921110110

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