High-resolution analysis of alterations in medullary thyroid carcinoma genomes.
Hereditary and sporadic medullary thyroid carcinoma (MTC) are closely associated with RET proto-oncogene mutations. However, the role of additional changes in the tumor genomes remains unclear. Our objective was the identification of chromosomal regions involved in MTC tumorigenesis and to assess their significance by using MTC-derived cell lines. We used array-CGH (comparative genomic hybridization) to map chromosomal imbalances in 52 primary tumors and ten metastases. Eleven tumors (11/52, 21%) were hereditary and 41 (41/52, 79%) were sporadic. Among the latter, 15 tumors (15/41, 37%) harbored RET mutations. Furthermore, we characterized five MTC cell lines in detail and evaluated the tumorigenicity by severe combined immunodeficiency (SCID)-mouse experiments. Most MTCs had only few copy number changes, and losses of chromosomes 1p, 4q, 19p and 22q were observed most frequently. The number of chromosomal aberrations increased in metastases. Twenty-three percent (12/52) of the primary tumors did not even show any chromosomal gains and losses. We injected three cell lines (two of these were without chromosomal changes and pathogenic RET mutations) into immune deficient SCID mice, and in each case, we observed rapid tumor growth at the injection sites. Our data suggest that MTCs--in contrast to most other tumor entities--do not acquire a multitude of genomic imbalances. SCID mouse experiments performed with chromosomally normal cell lines and without RET mutations suggest that presently unknown submicroscopic genomic changes are sufficient in MTC tumorigenesis.
Institute of Human Genetics, Medical University of Graz, Graz, Austria.
Karin
K
Flicker
Peter
P
Ulz
Harald
H
Höger
Petra
P
Zeitlhofer
Oskar A
OA
Haas
Annemarie
A
Behmel
Wolfgang
W
Buchinger
Christian
C
Scheuba
Bruno
B
Niederle
Roswitha
R
Pfragner
Michael R
MR
Speicher
D000818:Animals; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology; D018278:Carcinoma, Neuroendocrine; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D014183:Transplantation, Heterologous
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret