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CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome
T Frisk1, J Zedenius, J Lundberg
1Department of Molecular Medicine, Endocrine Tumor Unit, Karolinska Hospital CMM L8:01, SE-171 76 Stockholm, Sweden. tony.frisk@cmm.ki.se
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.
Insights
Medullary thyroid carcinoma (MTC) is linked to RET proto-oncogene mutations. This study found chromosomal imbalances in 60% of MTCs, with specific regions like 19q and 13q potentially involved in tumor development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Medullary thyroid carcinoma (MTC) tumorigenesis has primarily been linked to the RET proto-oncogene.
- Germline RET mutations are prevalent in familial MTC, while somatic RET mutations, specifically the M918T alteration, are common in sporadic MTC.
Purpose of the Study:
- To investigate chromosomal imbalances in medullary thyroid carcinoma (MTC) using comparative genomic hybridization (CGH).
- To correlate chromosomal alterations with clinical outcomes and RET proto-oncogene (RET) mutations in MTC.
Main Methods:
- Comparative genomic hybridization (CGH) was performed on 24 MTC samples to detect chromosomal imbalances.
- Statistical analysis was used to correlate CGH findings with patient survival and the presence of the RET M918T mutation.
Main Results:
- Chromosomal alterations were detected in approximately 60% of MTC samples.
- The most frequent aberrations included gains on chromosomes 19q, 19p, 11q, and 22q, and losses on 13q and 3q.
- Gain of chromosome 11q was significantly associated with poorer patient outcomes (p=0.001) and was more common in tumors with the RET M918T mutation.
Conclusions:
- Medullary thyroid carcinoma (MTC) appears to be a genetically stable tumor.
- Chromosomal regions 19q, 19p, 13q, and 11q are implicated in MTC carcinogenesis.
- Specific chromosomal gains, particularly on 11q, may serve as prognostic markers in MTC.