Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells

Research output: Contribution to journalArticle

Abstract

Cytogenetic and molecular analyses of thyroid tumors have indicated that these neoplasms represent a good model for analyzing human epithelial cell multistep carcinogenesis. They comprise, in fact, a broad spectrum of lesions with different phenotypes and variable biological and clinical behavior. Molecular analysis has detected specific genetic alterations in the different types of thyroid tumors. In particular, the well-differentiated carcinomas of the papillary type are characterized by activation of the receptor tyrosine kinases (RTKs), RET and NTRKI proto-oncogenes. Cytogenetic analysis of these tumors has contributed to defining the chromosomal mechanisms leading to RTK ontogenic activation. In the majority of cases, intrachromosomal inversions of chromosome 10 and chromosome 1 led to the formation of RET-derived and NTRKI-derived oncogenes, respectively. Interestingly, molecular analysis of these oncogenes revealed their nature of chimeric fusion proteins all sharing the tyrosine kinase (TK) domains of the respective proto-oncogenes. Moreover, the sequencing of the oncogenic rearrangements led to the identification of a breakpoint cluster region in both RTK proto-oncogenes. Exposure to ionizing radiation is associated with papillary carcinomas and RET activation has been suggested to be related to this event. Conversely, RAS point mutations are frequently observed in tumors with follicular histology and have been associated with metastatic dissemination. Iodide-deficient areas seem to provide a higher frequency of RAS positive follicular carcinomas. Finally, a high prevalence of TP53 point mutations has been detected only in undifferentiated or anaplastic carcinomas and found to correlate inversely with BCL2 expression. All of these findings are contributing to the definition of genetic and environmental factors relevant for the pathogenesis of thyroid tumors. Moreover, the characterization of specific genetic lesions could provide significant molecular tools for a better differential diagnosis and for the development of novel therapeutic avenues for thyroid cancer.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalGenes Chromosomes and Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - May 1996

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Cytogenetics
Molecular Biology
Carcinoma
Proto-Oncogenes
Neoplasms
Thyroid Gland
Papillary Carcinoma
Cytogenetic Analysis
Receptor Protein-Tyrosine Kinases
Oncogenes
Point Mutation
Proto-Oncogene Proteins c-ret
Chromosomes, Human, Pair 10
Chromosomes, Human, Pair 1
Iodides
Ionizing Radiation
Thyroid Neoplasms
Protein-Tyrosine Kinases
Thyroid Epithelial Cells
Histology

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

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title = "Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells",
abstract = "Cytogenetic and molecular analyses of thyroid tumors have indicated that these neoplasms represent a good model for analyzing human epithelial cell multistep carcinogenesis. They comprise, in fact, a broad spectrum of lesions with different phenotypes and variable biological and clinical behavior. Molecular analysis has detected specific genetic alterations in the different types of thyroid tumors. In particular, the well-differentiated carcinomas of the papillary type are characterized by activation of the receptor tyrosine kinases (RTKs), RET and NTRKI proto-oncogenes. Cytogenetic analysis of these tumors has contributed to defining the chromosomal mechanisms leading to RTK ontogenic activation. In the majority of cases, intrachromosomal inversions of chromosome 10 and chromosome 1 led to the formation of RET-derived and NTRKI-derived oncogenes, respectively. Interestingly, molecular analysis of these oncogenes revealed their nature of chimeric fusion proteins all sharing the tyrosine kinase (TK) domains of the respective proto-oncogenes. Moreover, the sequencing of the oncogenic rearrangements led to the identification of a breakpoint cluster region in both RTK proto-oncogenes. Exposure to ionizing radiation is associated with papillary carcinomas and RET activation has been suggested to be related to this event. Conversely, RAS point mutations are frequently observed in tumors with follicular histology and have been associated with metastatic dissemination. Iodide-deficient areas seem to provide a higher frequency of RAS positive follicular carcinomas. Finally, a high prevalence of TP53 point mutations has been detected only in undifferentiated or anaplastic carcinomas and found to correlate inversely with BCL2 expression. All of these findings are contributing to the definition of genetic and environmental factors relevant for the pathogenesis of thyroid tumors. Moreover, the characterization of specific genetic lesions could provide significant molecular tools for a better differential diagnosis and for the development of novel therapeutic avenues for thyroid cancer.",
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AU - Pierotti, Marco A.

AU - Bongarzone, Italia

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AU - Pilotti, Silvana

AU - Sozzi, Gabriella

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