CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome.

Department of Molecular Medicine, Endocrine Tumor Unit, Karolinska Hospital CMM L8:01, SE-171 76 Stockholm, Sweden.
International Journal of Oncology (Impact Factor: 2.66). 06/2001; 18(6):1219-25.
Source: PubMed

ABSTRACT Apart from the RET proto-oncogene (RET) no other genes have been found to be involved in medullary thyroid carcinoma (MTC) tumorigenesis. Germline RET mutations are seen virtually in all familial forms of MTC and somatic RET mutations are often detected in sporadic MTC. In sporadic MTCs the RET gene is mutated in codon 918, where a methionine is substituted to a threonine (M918T). In this study 24 MTCs were analyzed by comparative genomic hybridization (CGH) for chromosomal imbalances. Overall, alterations were detected in approximately 60% of the samples. The most common aberrations were gains on chromosome 19q (29%), 19p (21%), 11c-q12 (12.5%), and 22q (12.5%) and losses on 13q21 (21%) and 3q23-qter (12.5%). Gain of chromosome 11c-q12 was only detected in samples from patients whom died of MTC (p=0.001). These MTCs also harbored the somatic RET M918T mutation and also showed the highest numbers of CGH alterations in the series (p<0.003). Although there was a tendency towards a higher number of CGH imbalances in the tumors with RET M918T mutation, this difference was not significant. The results indicate that MTC is a comparatively genetically stable tumor, and that chromosomal regions 19q, 19p, 13q and 11q may be involved in MTC carcinogenesis.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    International Journal of Cancer 10/2011; 131(2):E66-73. · 6.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genetic alterations in human cancers and murine models indicate that retinoblastoma (Rb) and p53 have critical tumor suppressive functions in retinoblastoma, a tumor of neural origin, and neuroendocrine tumors including small cell lung cancer and medullary thyroid cancer (MTC). Rb inactivation is the initiating lesion in retinoblastoma and current models propose that induction of apoptosis is a key p53 tumor suppressive function. Genetic studies in mice, however, indicate that other undefined p53 tumor suppressive functions are operative in vivo. How p53 loss cooperates with Rb inactivation to promote carcinogenesis is also not fully understood. In the current study, genetically engineered mice were generated to determine the role of Rb and p53 in MTC pathogenesis and test the hypothesis that p53 suppresses carcinogenesis by inhibiting mammalian target of rapamycin (mTOR) signaling. Conditional Rb ablation resulted in thyroid tumors mimicking human MTC, and additional p53 loss led to rapid tumor progression. p53 suppressed tumorigenesis by inhibiting cell cycle progression, but did not induce apoptosis. On the contrary, p53 loss led to increased apoptosis that had to be overcome for tumor progression. The mTOR activity was markedly increased in p53-deficient tumors and rapamycin treatment suppressed tumor cell growth, identifying mTOR inhibition as a critical p53 tumor suppressive function. Rapamycin treatment did not result in AKT/mitogen-activated protein kinase activation, providing evidence that this feedback mechanism operative in other cancers is not a general response to mTORC1 inhibition. Together, these studies provide mechanistic links between genetic alterations and aberrant signaling pathways critical in carcinogenesis, and identify essential Rb and p53 tumor suppressive functions in vivo.Oncogene advance online publication, 27 January 2014; doi:10.1038/onc.2013.589.
    Oncogene 01/2014; · 8.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Association between DNA alterations and clinical parameters as recurrence, survival or prognosis has been found in a variety of tumors. A clear association between Medullary Thyroid Carcinoma (MTC) and RET oncogene mutation has been accepted. Specifically M918T RET mutation represents the main genetic event in most cases of sporadic MTC (SMTC) and limited chromosomal alterations analyses have been performed. In the present work, a comparative genomic hybridization (CGH) study was performed using DNA from a primary tumor in a M918T RET mutation-positive SMTC patient and from its lymph node metastasis to investigate additional genetic alterations. We studied a patient with 15 years of follow-up and persistence of disease, confirmed by periodical elevated serum calcitonin (CT) levels. Only 3 chromosomal imbalances were identified in the primary tumor, gain of 18p, and loss of 6p and 16p region, whereas 25 chromosomal imbalances were identified in the metastasis (9 gains and 16 losses). The chromosomal changes 6p-, 16p-, 18p + could determine in part the oncogenic phenotype in the primary M918T RET positive tumor and probably related to persistence of high serum CT levels in this patient. The additional chromosomal changes observed could be related to the metastasis phenotype. We suggest that some genes mapped at 6p, 16p and 18p chromosomal regions, could act as genes associated to cancer and could be related to persistent SMTC and good prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:
    Diagnostic Pathology 06/2012; 7:63. · 1.85 Impact Factor