DNA Copy Number Changes in Thyroid Carcinoma

Abstract

The genetic changes leading to thyroid cancer are poorly characterized. We studied DNA copy number changes by comparative genomic hybridization (CGH) in 69 primary thyroid carcinomas. In papillary carcinoma , DNA copy number changes were rare (3 of 26 , 12%). The changes were all gains , and they were associated with old age (P ‫؍‬ 0.01) and the presence of cervical lymph node metastases at presentation (P ‫؍‬ 0.08). DNA copy number changes were much more frequent in follicular carcinoma (16 of 20, 80%) than in papillary carcinoma (P < 0.0001), and follicular carcinomas had more often deletions (13/20 versus 0/26 , P < 0.0001). Loss of chromosome 22 was common in follicular carcinoma (n ‫؍‬ 7 , 35%) , it was more often seen in widely invasive than in minimally invasive follicular carcinoma (54% versus 0% , P ‫؍‬ 0.04) , and it was associated with old age at presentation (P ‫؍‬ 0.01). In three of the four patients with follicular carcinoma who died of cancer , the tumor had loss of chromosome 22. DNA copy number changes were found in 5 (50%) of the 10 medullary carcinomas studied. Four of these five carcinomas had deletions , and in two of them there was deletion of chromosome 22. Eleven (85%) of the thirteen anaplastic carcinomas investigated had DNA copy number changes , of which five had deletions , and one had deletion of chromosome 22. The most common gains in anaplastic carcinoma were in chromosomes 7p (p22-pter , 31%) , 8q (q22-qter , 23%) , and 9q (q34-qter , 23%). We conclude that DNA copy number changes are frequent in follicular , medullary, and anaplastic thyroid carcinoma but rare in papillary carcinoma when studied by CGH. Loss of chromosome 22 is particularly common in follicular carcinoma , and it is associated with the widely invasive type. (Am J Pathol 1999, 154:1539 -1547)The great majority of all thyroid cancers are either papillary, follicular, or anaplastic carcinomas, which are thought to be derived from follicular cells. Only 5% to 10% are medullary carcinomas, which originate from the C-cells.1 This histopathological classification of thyroid carcinomas into four major subtypes has been considered as established, and each of the four entities have typical clinical features. Papillary carcinoma frequently gives rise to cervical lymph node metastases, but distant metastases are rare. This pattern is reversed in follicular carcinoma, which often has distant bone metastases, but cervical lymph node metastases are rare. Papillary and follicular carcinoma are frequently found in the same thyroid as anaplastic carcinoma, suggesting that some anaplastic carcinomas originate from pre-existing differentiated carcinoma. 2,3The molecular genetic events in the evolution of different types of thyroid carcinomas are poorly characterized. However, the central role of mutations in the RET protooncogene, located at 10q11.2, in the genesis of hereditary medullary thyroid carcinoma is now well recognized, and used in screening of this disorder. More than 95% of patients with MEN 2A have missense germ line mu...

Poorly differentiated and anaplastic thyroid carcinomas: chromosomal and oligo-array profile of five new cell lines

“…Comparison of our PDTC and ATC CGH results with previously reported data (Hemmer et al, 1999;Wilkens et al, 2000;Wreesmann et al, 2002;Rodrigues et al, 2004) revealed that all imbalances, described as frequently occurring in the literature, were also observed in the cell lines.…”

“…The chromosomal gains and losses observed for each of the cell lines and respective primary tumours were represented in an excel table (CGH supplementary data). Analysis of these data allowed to verify that although CGH alterations observed in the cell lines were not identical to the ones found in primary tumours, they presented major similarities, indicating that these cell lines largely reflect their primary tumour major cytogenetic imbalances.Comparison of our PDTC and ATC CGH results with previously reported data (Hemmer et al, 1999;Wilkens et al, 2000;Wreesmann et al, 2002;Rodrigues et al, 2004) revealed that all imbalances, described as frequently occurring in the literature, were also observed in the cell lines. …”

Clonal chromosomal aberrations in simian virus 40‐transfected human thyroid cells and in derived tumors developed after in vitro irradiation

“…Although they probably imply significant genetic changes, it is likely that they were not sufficient to cause the aggressive malignant phenotype since they occurred also in the nontumorigenic lines. It is, however, of interest that recent CGH and loss of heterozygosity (LOH) studies on follicular carcinomas [36,37] and Hürthle cell tumors [38] of the thyroid gland revealed the same aberrations (losses on chromosomes 13q and 9q31-q33, gains on chromosomes 1q and 20) as this model cell system of radiation-induced transformation of epithelial thyroid cells.…”

Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer

“…Therefore, although there are different reports of overexpression of Skp2 protein in human haematological and solid cancers (Gstaiger et al 2001, Kudo et al 2001, Latres et al 2001, Chiarle et al 2002, Masuda et al 2002, Signoretti et al 2002, Li et al 2004, so far there are no studies regarding the clinical significance or the biological behaviour of Skp2 expression in human thyroid carcinomas. Most interestingly, genetic alterations that result in gain of part or of the entire short arm of chromosome 5, where the Skp2 gene has been assigned at 5p13, frequently occur in PTC, Hurthle carcinomas and ATC (Hemmer et al 1999,Wada et al 2002, Foukakis et al 2005, suggesting that Skp2 may be the target of gene amplification in a fraction of thyroid cancer.…”