Not Only but and Chromosomal Instability Are Seen in Young Patients with Sporadic Medullary Thyroid Carcinoma.

CONTEXT

Genetic analysis of sporadic medullary thyroid carcinoma (MTC) has revealed somatic variants in , , and occasionally other genes. However, around 20% of patients with sporadic MTC lack a known genetic driver.

OBJECTIVE

To uncover potential new somatic or germline drivers, we analyze a distinct cohort of patients with sporadic, very early-onset, and aggressive MTC.

METHODS

Germline and somatic DNA exome sequencing was performed in 19 patients, previously tested negative for germline variants.

RESULTS

Exome sequencing of 19 germline samples confirmed the absence of and identified an pathogenic variant in 1 patient. Somatic sequencing was successful in 15 tumors revealing variants in 80%, predominantly p.Met918Thr, which was associated with disease aggressiveness. In -negative tumors, pathogenic variants were found in and . The germline and somatic variants were observed in a patient without a prior clinical diagnosis of neurofibromatosis type 1, demonstrating that the loss of heterozygosity of functions as a potential MTC driver. Somatic copy number alterations analysis revealed chromosomal alterations in 53.3% of tumors, predominantly in -positive cases, with losses in chromosomes 9 and 22 being the most prevalent.

CONCLUSION

This study reveals that within a cohort of early-onset nonhereditary MTC, remains the major driver gene. In -negative tumors, and are drivers of sporadic MTC. In addition, in young patients without a germline mutation, a careful clinical evaluation with a consideration of germline gene analysis is ideal to exclude Neurofibromatosis type 1 (NF1).