Different genetic landscapes of papillary thyroid carcinoma and paired benign nodules revealed by integrated multi-omics analysis

Abstract

Abstract Background: Alterations in the genetic landscape of papillary thyroid carcinoma (PTC) compared with coincidental benign thyroid nodules, especially adenomatoid nodules, remain to be demonstrated. Methods: Multi-omics profiling of whole-exome sequencing, assay for transposase-accessible chromatin using sequencing (ATAC-seq), and transcriptome sequencing were used for analysis. Results: Chromatin accessibility in the PTC was lower than that in the benign nodules around the transcription start sites (distance <1 kb) with high interpatient heterogeneity of chromatin profiles and distinct open chromatin accessibility. The gene regions around the mutation loci that were only detected in PTC exhibited altered chromatin accessibility between the PTC and benign nodules. Through integrated ATAC-Seq and RNA-Seq analysis, ARHGEF28 and ARHGEF24, genes not previously related to PTC or adenomatoid nodules, were identified. They were overexpressed and hyperaccessible in adenomatoid nodules compared to those in PTC. They were regulated by TEAD4, and hyperaccessible binding sites were enriched in differentially accessible regions in benign nodules. In addition, extrachromosomal circular DNA (eccDNA) analysis derived from ATAC-sequencing showed indolent character, but no PTC-diver genes in the eccDNA was found. Conclusions: This compendium of multi-omics data provides valuable insights and a resource for understanding the landscape of open chromatin features and regulatory networks in PTC and benign nodule pathogeneses.