Genomic investigation of primary and metastatic medullary thyroid carcinoma
Roxanna Mortazavi, Samuel Backman, Olov Norlén, Matilda Annebäck, Elham Barazeghi, Peter Stålberg, Tobias ÅkerströmAbstract
Introduction
Medullary thyroid carcinoma (MTC) is primarily driven by mutations in the RET proto-oncogene. Intratumoral heterogeneity is an important feature of tumor progression, and epigenetic alterations are increasingly recognized as potential contributors. However, their roles in MTC remain insufficiently studied. This study aimed to investigate genetic changes in advanced disease by examining intratumoral heterogeneity in primary and metastatic lesions of MTC.
Methods
Whole-genome sequencing was performed on 29 tumor samples from primary and metastatic lesions in 11 patients with sporadic MTC. Somatic mutations, copy number alterations (CNVs) and structural variants were analyzed.
Results
We identified somatic RET mutations in 9 of 11 (82%) patients, present in primary and metastatic lesions, and a germline RET mutation was confirmed in one patient. Large CNVs were identified in 9 of 11 tumors, and in 4 patients these occurred heterogeneously. Mutations in KMT2D, an epigenetic regulator, were found in 4 of 11 (36%) patients. Two were truncating, with one showing loss of heterozygosity and the other allelic imbalance. The remaining two were missense mutations, one affecting a functionally important domain. KMT2D mutations were primarily observed in metastatic lesions.
Discussion
Large CNVs were frequent but often heterogeneous, suggesting that they may not be necessary for metastatic potential. KMT2D mutations were observed in a subset of tumors and were more frequent in metastatic tissue, indicating that they may arise at a later stage in tumor evolution and contribute to progression. These findings highlight the role of intratumoral heterogeneity in advanced disease and support the need for validation in larger cohorts.