Integrated Genomic Characterization of Papillary Thyroid Carcinoma

Abstract

Summary Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

Genetic effects on gene expression across human tissues

“…Despite the ambiguity of cis -mediation, the locus is one of the strongest trans -eQTL signals in GTEx. We further replicated both the broad regulatory effect and specific target genes of this locus in 498 primary thyroid cancer RNA-seq samples from The Cancer Genome Atlas 50 (TCGA; Fig. 6b, Supplementary Information 18).…”

Identification of novel cyclin gene fusion transcripts in endometrioid ovarian carcinomas

“…Fusion junctions of the chimeric transcripts found in ( a ) CCC, ( b ) HGSC, and ( c ) EC of the present series and fusion transcripts from the literature involving one of the gene with different partners or the same genes with different breakpoints 5, 33, 35. The asterisk (*) indicates the fusion transcripts detected in the present series.…”

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

“…Pathogenetic role of the mutation has been widely proved by pre-clinical studies ). According to the TCGA, BRAF V600E largely represents the most common driver mutational event involved in PTC (58.5% of the cohort) (Agrawal et al 2014). Unlike RET rearrangements, several authors reported a clear association of BRAF V600E with molecular features suggestive of biological and clinical aggressiveness.…”

“…Pathogenetic role of RET rearrangements in PTC has been elaborately described (Santoro et al 1993, Jhiang et al 1998, Tallini et al 1998, Powell et al 1998. Nevertheless, the TCGA study reported the occurrence of RET/PTC as a founder genetic event in only 6.8% of the PTC cohort (Agrawal et al 2014). This represented a breakthrough, as estimation of actual prevalence (Zhu …”

“…Based on the identified set of molecular abnormalities, the Thyroid Cancer Genome Atlas (TCGA) has recently performed a comprehensive genetic and epigenetic analysis of a large cohort of PTC samples by means of the most innovative next-generation sequencing (NGS) techniques (Agrawal et al 2014). Importantly, a great effort was made for attesting the driver role of identified mutations.…”