Whole-genome sequencing of follicular thyroid carcinomas reveal recurrent mutations in microRNA processing subunit DGCR8

Background The genomic and transcriptomic landscape of widely invasive follicular thyroid carcinomas (wiFTCs) is poorly characterized, and a large subset of these tumours lack information on credible genetic driver events. The aim of this study was to bridge this gap. Methods We performed whole-genome and RNA sequencing and subsequent bioinformatic analyses of 13 wiFTCs with a particularly poor prognosis, and matched normal tissue. Results Ten out of thirteen (77%) tumours exhibited one or several mutations in established genes ranked as the top 20 mutated in thyroid cancer, including TERT (n=4), NRAS (n=3), HRAS, KRAS, AKT, PTEN, PIK3CA, MUTYH and MEN1 (n=1 each). Recurrent somatic mutations in three genes were annotated as significant according to MutSig2CV: FAM72D (n=3), TP53 (n=3) and EIF1AX (n=3), with DGCR8 (n=2) as borderline significant. Of interest, both DGCR8 mutations were recurrent p.E518K missense alterations, a mutation known to cause familial multinodular goiter (MNG) via disruption of microRNA (miRNA) processing. Expression analyses pinpointed a trend towards reduced DGCR8 mRNA expression in FTCs in general. Copy number analyses revealed recurrent gains of loci on chromosomes 4, 6 and 10, and fusion gene analyses revealed 27 high-quality events. Based on the transcriptome data FTCs clustered in two principal clusters, displaying significant differences in expression of genes associated with metabolic pathways. Conclusion In summary, we describe the genomic and transcriptomic landscape in wiFTCs and identify novel recurrent mutations and copy number alterations with possible driver properties and lay the foundation for future studies. The dataset consists of tables and lists containing underlying data, and supplementary figures for a manuscript submitted to "Journal of Clinical Endocrinology & Metabolism". It includes 8 tables and 3 figures: File name: T1_Detailed-characteristics-of-the-study-cohort.csv Contains "Table 1: Detailed characteristics of the study cohort."  File name: T2_List-of-Somatic-SNVs.csv Contains "Table 2: List of Somatic SNV's (Small nucleotide variants)."  File name: T3_MutSig2CV-input-genes.csv Contains "Table 3: MutSig2CV input genes."  File name: T4_MutSig2CV-genes-ranked-by-p-value.csv Contains "Table 4: MutSig2CV genes ranked by p-value." File name: T5_Genes-in-copy-number-altered-minimal-region-of-amplification.csv Contains "Table 5: List of genes in copy number altered minimal region of amplification."  File name: T6_Aberrant-cell-fraction-and-ploidy-as-determined-by-ASCAT.csv Contains "Table 6: Aberrant cell fraction and ploidy as determined by ASCAT."  File name: T7_High-confidence-structural-variations-in-the-tumor-cohort.csv Contains "Table 7: List of high-confidence structural variations in the tumor cohort."  File name: T8_Significant-differentially-expressed-genes-in-tumor-vs-normal-thyroid.csv Contains "Table 8: List of significant differentially expressed genes in tumor versus normal thyroid." File name: List_of_variables.pdf Contains List of variables: Metadata and abbreviation explanations for Table 1-8. File name: Whole-genome-sequencing-follicular-thyroid-carcinomas_Figures.pdf Contains Supplementary Figure S1-S3: - Supplementary Figure S1: Somatic mutational overview in the WGS cohort.  - Supplementary Figure S2: Normalized DGCR8 mRNA expression in tumours with or without loss of heterozygosity (LOH) of the DGCR8 locus.  - Supplementary Figure S3: a Gene set enrichment analysis (GSEA).