Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

Abstract

The aim of this study is to investigate additional genetic alterations in papillary thyroid carcinomas (PTCs) with known RET/PTC rearrangements. We applied arraybased comparative genomic hybridization (array CGH) to 33 PTC (20 PTC from adults, 13 post-Chernobyl PTC from children) with known RET/PTC status. Principal component analysis and hierarchical cluster analysis identified cases with similar aberration patterns. Significant deviations between tumour-groups were obtained by statistical testing (Fisher's exact test in combination with Benjamini-Hochberg FDR-controlling procedure). FISH analysis on FFPE sections was applied to validate the array CGH data. Deletions were found more frequently in RET/PTC-positive and RET/PTC-negative tumours than amplifications. Specific aberration signatures were identified that discriminated between RET/PTC-positive and RET/PTC-negative cases (aberrations on chromosomes 1p, 3q, 4p, 7p, 9p/q, 10q, 12q, 13q and 21q). In addition, childhood and adult RET/PTC-positive cases differ significantly for a deletion on the distal part of chromosome 1p. There are additional alterations in RET/PTC-positive tumours, which may act as modifiers of RET activation. In contrast, alterations in RET/ PTC-negative tumours indicate alternative routes of tumour development. The data presented serve as a starting point for further studies on gene expression and function of genes identified in this study.

Chromosomal aberrations in thyroid follicular-cell neoplasia: in the search of novel oncogenes and tumour suppressor genes

“…In addition, Kitamura et al (2000) described an association of allelic losses of 1q, 4p, 9 and 16q with survival in PTC. More recent studies using array-CGH of specimen enriched for tumour cells by microdissection showed a more common appearance of copy number changes in PTC (Finn, et al 2007;Unger, et al 2008). In these studies, recurrent aberrations were reported which are in accordance with previous CGH studies and which discriminate RET/PTC-positive and -negative tumours (Unger et al 2008) or are typical for wildtype Ret or Braf tumours (Finn et al 2007).…”

“…More recent studies using array-CGH of specimen enriched for tumour cells by microdissection showed a more common appearance of copy number changes in PTC (Finn, et al 2007;Unger, et al 2008). In these studies, recurrent aberrations were reported which are in accordance with previous CGH studies and which discriminate RET/PTC-positive and -negative tumours (Unger et al 2008) or are typical for wildtype Ret or Braf tumours (Finn et al 2007). In focal papillary carcinoma with changes in follicular-patterned thyroid nodules trisomy 17 was identified which potentially reflects a specific marker of this subset of thyroid lesions (Frau, et al 2008).…”

Intratumor heterogeneity and clonal evolution in an aggressive papillary thyroid cancer and matched metastases

“…Similarly, Anaka et al (2013) have identified significant heterogeneity in chromosomal aberrations in different regions of a LN metastasis in a melanoma patient. As mentioned by others (Unger et al 2008, Gerlinger et al 2012, this molecular heterogeneity highlights the importance of sampling multiple areas of the same tumor to better ascertain the range of genomic alterations characterizing its progression. Indeed the heterogeneous presence of genomic alterations may impair patient genotyping and subsequent prognostic classification and targeted therapy.…”

Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice

“…Genomic reference DNA was labelled with Cy5 (Invitrogen) and co-hybridised to 1 Mb BAC mouse arrays (Chung et al 2004). DNA labelling, hybridisation and data processing were performed as described by Unger et al (2008). Further data analysis was performed using the web-based array CGH evaluation platform CAPweb , http://bioinfo.…”

“…For these CNA, we used the synteny approach on www.ensemble.org to define the syntenic human regions. These human regions were reconciled with array CGH data generated in our lab from human PTCs (Unger et al 2008, Hess et al 2011. We further determined candidate genes located in these altered regions from the published literature.…”