DNA repair pathway activation features in follicular and papillary thyroid tumors, interrogated using 95 experimental RNA sequencing profiles

Uliana Vladimirova; Pavel Rumiantsev; Marianna Zolotovskaia; Eugene Albert; Aleksander Abrosimov; Konstantin Slashchuk; Petr Nikiforovich; Olga Chukhacheva; Nurshat Gaifullin; Maria Suntsova; Galina Zakharova; Alexander Glusker; Daniil Nikitin; Andrew Garazha; Xinmin Li; Dmitriy Kamashev; Alexei Drobyshev; Irina Kochergina-Nikitskaya; Maxim Sorokin; Anton Buzdin

doi:10.1016/j.heliyon.2021.e06408

DNA repair pathway activation features in follicular and papillary thyroid tumors, interrogated using 95 experimental RNA sequencing profiles

Heliyon. 2021 Mar 13;7(3):e06408. doi: 10.1016/j.heliyon.2021.e06408. eCollection 2021 Mar.

Authors

Uliana Vladimirova^{1

2}, Pavel Rumiantsev^{3

2}, Marianna Zolotovskaia², Eugene Albert⁴, Aleksander Abrosimov³, Konstantin Slashchuk³, Petr Nikiforovich³, Olga Chukhacheva³, Nurshat Gaifullin⁵, Maria Suntsova¹, Galina Zakharova³, Alexander Glusker¹, Daniil Nikitin^{4

6}, Andrew Garazha⁴, Xinmin Li⁷, Dmitriy Kamashev¹, Alexei Drobyshev¹, Irina Kochergina-Nikitskaya⁶, Maxim Sorokin^{1

4

8}, Anton Buzdin^{1

4

8

6}

Affiliations

¹ I.M. Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
² Pirogov Russian National Research Medical University, Moscow, 117997, Russia.
³ Endocrinology Research Centre, Moscow, 117312, Russia.
⁴ Omicsway Corp., Walnut, CA, 91789, USA.
⁵ Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 119992, Russia.
⁶ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
⁷ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA.
⁸ Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.

Abstract

DNA repair can prevent mutations and cancer development, but it can also restore damaged tumor cells after chemo and radiation therapy. We performed RNA sequencing on 95 human pathological thyroid biosamples including 17 follicular adenomas, 23 follicular cancers, 3 medullar cancers, 51 papillary cancers and 1 poorly differentiated cancer. The gene expression profiles are annotated here with the clinical and histological diagnoses and, for papillary cancers, with BRAF gene V600E mutation status. DNA repair molecular pathway analysis showed strongly upregulated pathway activation levels for most of the differential pathways in the papillary cancer and moderately upregulated pattern in the follicular cancer, when compared to the follicular adenomas. This was observed for the BRCA1, ATM, p53, excision repair, and mismatch repair pathways. This finding was validated using independent thyroid tumor expression dataset PRJEB11591. We also analyzed gene expression patterns linked with the radioiodine resistant thyroid tumors (n = 13) and identified 871 differential genes that according to Gene Ontology analysis formed two functional groups: (i) response to topologically incorrect protein and (ii) aldo-keto reductase (NADP) activity. We also found RNA sequencing reads for two hybrid transcripts: one in-frame fusion for well-known NCOA4-RET translocation, and another frameshift fusion of ALK oncogene with a new partner ARHGAP12. The latter could probably support increased expression of truncated ALK downstream from 4^th exon out of 28. Both fusions were found in papillary thyroid cancers of follicular histologic subtype with node metastases, one of them (NCOA4-RET) for the radioactive iodine resistant tumor. The differences in DNA repair activation patterns may help to improve therapy of different thyroid cancer types under investigation and the data communicated may serve for finding additional markers of radioiodine resistance.

Keywords: DNA repair; Follicular thyroid adenoma; Molecular biomarkers; Molecular pathway analysis; Papillary thyroid cancer; Personalized medicine; RNA sequencing; Radiation iodine therapy resistance; Systems biology; Thyroid cancer.

Grants and funding

P30 CA016042/CA/NCI NIH HHS/United States