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

Apart from the RET proto-oncogene (RET) no other genes have been found to b e 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 hybridi zation (CGH) for chromosomal imbalances. Overall, alterations were detected in approximately 60% of the samples. The most common aberrations were gain s on chromosome 19q (29%), 19p (21%, 11c-q12 (12.5%), and 22q (12.5%) and l osses on 13q21 (21%) and 3q23-qter (12.5%). Gain of chromosome l1c-q12 was only detected in samples from patients whom died of MTC (p=0.001). These MT Cs 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 M 918T mutation, this difference was not significant. The results indicate th at MTC is a comparatively genetically stable tumor, and that chromosomal re gions 19q, 19p, 13q and 11q may be involved in MTC carcinogenesis.