Molecular signatures of thyroid follicular neoplasia

Abstract

The molecular pathways leading to thyroid follicular neoplasia are incompletely understood, and the diagnosis of follicular tumors is a clinical challenge. To provide leads to the pathogenesis and diagnosis of the tumors, we examined the global transcriptome signatures of follicular thyroid carcinoma (FC) and normofollicular adenoma (FA) as well as fetal/microFA (fetal adenoma). Carcinomas were strongly enriched in transcripts encoding proteins involved in DNA replication and mitosis corresponding to increased number of proliferating cells and depleted number of transcripts encoding factors involved in growth arrest and apoptosis. In the latter group, the combined loss of transcripts encoding the nuclear orphan receptors NR4A1 and NR4A3, which were recently shown to play a causal role in hematopoetic neoplasia, was noteworthy. The analysis of differentially expressed transcripts provided a mechanism for cancer progression, which is why we exploited the results in order to generate a molecular classifier that could identify 95% of all carcinomas. Validation employing public domain and cross-platform data demonstrated that the signature was robust and could diagnose follicular nodules originating from different geographical locations and platforms with similar accuracy. We came to the conclusion that down-regulation of factors involved in growth arrest and apoptosis may represent a decisive step in the pathogenesis of FC. Moreover, the described molecular pathways provide an accurate and robust genetic signature for the diagnosis of FA and FC.

Down-regulation of microRNAs controlling tumourigenic factors in follicular thyroid carcinoma

“…The resemblance to AC may not be surprising, because there is a substantial overlap between the miRNAs that change in FC and those altered in AC (Braun et al 2010). Moreover, in a PCA of all genes, FCs tend to distribute as a continuum ranging from relatively well-differentiated FCs to FCs that are located in close proximity to ACs in contrast to papillary cancers that form their own homogenous group (Borup et al 2010). The common changes in miRNAs may also be interpreted as an indication that FC and ACs share a common tumourigenic pathway that differs from the papillary cancers.…”

“…The global mRNA expression data originating from FA, FC and AC tissue samples was based on previous work by our group (Borup et al 2010). In addition, mRNA profiles of papillary and NT tissue samples were down loaded from the Array Express, ID: E-GEOD-6004 and E-GEOD-7307 respectively.…”

Unsupervised analysis of follicular thyroid tumours transcriptome by oligonucleotide microarray gene expression profiling

“…There have been a number of genomic studies dealing with the classification of follicular thyroid tumours by genomic tests [17][18][19][20][21][22]. The recent paper by Alexander et al provides a clinically useful tool to discriminate gene expression patterns of thyrocytes even in fine-needle aspiration biopsy [23][24].…”

Classification of follicular cell-derived thyroid cancer by global RNA profiling

“…We showed FTC to be characterised by increased levels of mRNAs encoding proteins involved in DNA replication and mitosis, TOP2A, aniline (ANLN), PDZ-binding kinase (PBK) and abnormal spindle-like microcephaly-associated protein (ASPM) (Borup et al 2010). TOP2A is an enzyme that alters the topologic states of DNA in the transcription phase and its dysregulation can cause chromosomal instability.…”

“…TOP2A is of particular interest as it represents a possible treatment target (Pritchard et al 2008, O'Malley et al 2009). Additionally, we found loss of transcripts encoding proteins involved in growth arrest and apoptosis such as FBJ murine osteosarcoma viral oncogene homologue B (FOSB), JUN proto-oncogene (JUN), NR4A1 and NR4A3 (nuclear receptor subfamily 4, group A, member 1 and member 3) (Borup et al 2010). Members of the orphan nuclear receptor family, NR4A1 and NR4A3, were studied both in vivo and in vitro by Mullican et al (2007), who established their role as critical tumour suppressors in cancer.…”