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

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Mikhail Raevskiy^1,2,a, Maxim Sorokin^3,4,5,b, Uliana Vladimirova^3,c, Maria Suntsova^3,5,d, Victor Efimov^2,e, Andrew Garazha^1,f, Alexei Drobyshev^3,5,g, Aleksey Moisseev^5,h, Pavel Rumiantsev^6,i, Xinmin Li^7,j, and Anton Buzdin^1,2,3,5,k*

¹Omicsway Corp., 340 S Lemon Ave, 6040, Walnut, 91789 CA, USA

²Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia

³Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia

⁴Oncobox Ltd., 121205 Moscow, Russia

⁵Sechenov First Moscow State Medical University, 119991 Moscow, Russia

⁶Endocrinology Research Centre, 117312 Moscow, Russia

⁷Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, 90095 USA

^* To whom correspondence should be addressed.

Received August 2, 2021; Revised October 1, 2021; Accepted October 1, 2021

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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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KEY WORDS: mutation, EGFR, BRAF V600E transcriptomic biomarker, RNA sequencing, papillary thyroid cancer

DOI: 10.1134/S0006297921110110

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