Genome-Wide Appraisal of Thyroid Cancer Progression

Abstract

Several lines of evidence suggest that follicular cellderived thyroid cancers represent a continuum of disease that progresses from the highly curable welldifferentiated thyroid cancers to the universally fatal anaplastic cancers. However, the genetic mechanisms underlying thyroid cancer progression remain ill defined. We compared the molecular-cytogenetic profiles derived from comparative genomic hybridization (CGH) analysis of major histological variants of thyroid cancer to define genetic variables associated with progression. Overall, a sequential increase in chromosomal complexity was observed from welldifferentiated papillary thyroid cancer to poorly differentiated and anaplastic carcinomas, both in terms of the presence of CGH detectable abnormalities (P ‫؍‬ 0.003) and the median number of abnormalities per case (P < 0.001). The presence of multiple abnormalities common to all thyroid cancer variants, including gains of 5p15, 5q11-13, 19p, and 19q and loss of 8p, suggests that these tumors are derived from a common genetic pathway. Gains of 1p34 -36, 6p21, 9q34, 17q25, and 20q and losses of 1p11-p31, 2q32-33, 4q11-13, 6q21, and 13q21-31 may represent secondary events in progression, as they were only detected in poorly differentiated and anaplastic carcinomas. Finally, recurrent gains at 3p13-14 and 11q13, and loss of 5q11-31 were unique to anaplastic carcinomas, suggesting they may be markers for anaplastic transformation. Our data suggests that the development of chromosomal instability underlies the progression to more aggressive phenotypes of thyroid cancer and sheds light on the possible genomic aberrations that may be selected for during this process.

Histopathologic characterization of radioactive iodine‐refractory fluorodeoxyglucose‐positron emission tomography‐positive thyroid carcinoma

“…Indeed, our group showed that the median number of chromosomal abnormalities per case rises from 1 in well-differentiated PTC to 10 in anaplastic carcinoma, with intermediate values of 3 and 5 for TCV and PDTC, respectively. 17 In a minority of cases, morphologic instability was best demonstrated in cases in which the metastasis demonstrated a betterdifferentiated histology compared with the primary tumor. This phenomenon has been previously reported in bone metastases from thyroid carcinomas.…”

BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment

“…Compared to well-differentiated carcinomas, anaplastic thyroid carcinomas are more likely to be aneuploid, 5 they demonstrate a much higher prevalence of loss of heterozygosity, 1,6 and they harbor alterations of key regulators of cell growth and differentiation that are not targeted in earlier stages of tumorigenesis. 7,8 As one example, mutations of p53 are commonly noted in anaplastic thyroid carcinomas, but they are rarely present in well-differentiated thyroid carcinomas. [9][10][11][12] BRAF encodes a serine-threonine kinase that acts in the mitogen activated protein kinase (MAPK) pathway.…”

Detection and molecular characterisation of thyroid cancer precursor lesions in a specific subset of Hashimoto's thyroiditis

“…Molecular and immunohistochemical studies directed to detect specific gene profiles and related proteins in thyroid cancer have been extensively reported in literature (Bartolazzi et al, 2001;Huang et al, 2001;Ruco et al, 2001;Wreesmann et al, 2002). Experimental data, mostly arising from the molecular analysis of papillary thyroid carcinoma (PTC), contributed to identify a panel of genes overexpressed in thyroid malignancy.…”