Genetic and epigenetic predictors of tongue squamous cell carcinoma sensitivity to platinum drugs

Background. Treatment of locally advanced malignant tumors of the tongue at the present stage of development of clinical oncology is a difficult task and is an important problem in oncology. The aim — to screen for genetic and epigenetic predictors of locally advanced tongue cancer sensitivity to platinum therapy. Methods. A comprehensive clinical and molecular genetic examination was carried out in 100 patients with locally advanced malignant tumors of the tongue, as well as 30 donors without oncological pathology. The study used a new method for the treatment of locally advanced squamous cell carcinoma of the tongue using 2-stage superselective embolization as a component of complex treatment. At the first stage, a screening bioinformatics analysis was carried out to form a panel of genetic loci associated with sensitivity to therapy with platinum drugs. The determination of the relative copy number and expression of these loci responsible for repair and for the proliferation regulation and apoptosis was performed by Real-Time qPCR. Results. Integration of RNA-seq datasets, copy number variation data, and relevant clinicopathological information from TCGA and GEO databases allowed us to identify 65 genetic loci associated with sensitivity to platinum therapy. These genes were validated in patient biological material. Laboratory screening showed differential expression of BRCA1, BLM, ERCC1, EXO1, RAD50, PIF1, LIG1, BCL2, ERBB2, MAGEH1, NGFRAP1, and CASP8 genes, correlating with changes in their tissue copy numbers, between groups of patients sensitive and resistant to platinum therapy. The profile of gene copy numbers of BRCA1, BLM, EXO1, RAD50, PIF1, LIG1, CASP8, MAGEH1 and NGFRAP1 was detected in the blood plasma of patients with squamous cell carcinoma of the tongue, which was differential for two groups of patients — sensitive and resistant to platinum therapy. Based on bootstrap models, the final gene panel was obtained: BLM/NGFRAP1, BRCA1/MAGEH1, EXO1/RAD50, BLM/CASP8, BRCA1/RAD50 and BRCA1/EXO1, providing diagnostic sensitivity at the level of 95% and specificity at the level of 90% (AUC 0.98) when dividing patients into a group sensitive and resistant to platinum therapy. Conclusion. Comprehensive bioinformatics analysis of RNA sequencing data, gene copy number data, and clinical and pathological information from the TCGA and GEO databases, as well as laboratory screening of potential predictors, allowed us to obtain a panel of genes — BLM/NGFRAP1, BRCA1/MAGEH1, EXO1/RAD50, BLM/CASP8, BRCA1/RAD50, and BRCA1/EXO1, the combination of which provides high diagnostic sensitivity and specificity in dividing patients into a group susceptible and resistant to platinum therapy.