Clinical

Target treatment effect on mutant genes in childhood thyroid cancer



Compared to adults, thyroid cancer in childhood and adolescence is often found to be more advanced. The recurrence rate is also high. A research team consisting of Kim Jong-il, a professor of biochemistry at Seoul National University Medical School (Director of Genetic Medicine Research Institute), Park Young-joo, a professor of pediatrics Lee Young-ah, and Lee Hyun-jung, a Ph.D. in pediatrics, identified the molecular genetic characteristics of papillary carcinoma.

The research team confirmed the targeted treatment effect on mutant genes in childhood thyroid cancer. After targeted therapy, tumor size decreased and radioisotope therapy effect increased. The researchers found that fusion gene mutations are higher in children than in adults through a large-scale comparative study of transcriptional bodies in children. As a result of checking the frequency of gene mutations according to the age of thyroid cancer in childhood and adolescence, the frequency of fusion gene mutations decreased to 92.9%, 27.5%, and 13.5%, with age under 10, 10-14 and 15-19 years old. The frequency of point mutations gradually increased.

Thyroid cancer in childhood and adolescence has a higher stage than adults at the time of diagnosis, so the rate of lymph nodes and lung metastasis is higher. The response to radioiodine treatment after surgery is good. Since there are cases in which radioiodine treatment is not responded to in advanced thyroid cancer, it was necessary to consider targeted therapy based on genetic mutations in tumors by analyzing molecular genetic characteristics of childhood thyroid cancer.

In adolescents, the frequency of BRAFV600E gene mutations was high similar to that of adults, but in young children, the frequency of fusion gene mutations (RET, TRK, ARK fusion, etc.) was high, unlike adults. When comparing transcriptome results in childhood and adult thyroid cancer, childhood thyroid cancer with fusion gene mutations had lower thyroid differentiation gene expression, including sodium-Iodine co-transporter-related SLC5A5, than adult thyroid cancer.

Despite radioactive iodine treatment, CCDC6-RET and TPR-NTRK1 mutations were confirmed in two young children with lung metastasis. The expression of SLC5A5 was low and the absorption rate of radioactive iodine in metastatic cancer tissues was low.

As a result of the treatment of selpercatinib and larotrectinib, which target RET and TRK mutations, respectively, in these children, the tumor size decreased and radioactive iodine was well absorbed into metastatic cancer.

Cell experiments showed a decrease in iodine absorption in TRK mutant-positive cells, with increased sodium-iodine co-transporter expression and significant increase in radioiodine absorption after administration of targeted treatments for TRK mutants.

This study is meaningful in that it suggested that targeting and radioiodine therapy can be an effective treatment strategy to first identify gene mutations that can be targeted in young children who do not respond to radioiodine therapy. This study is expected to greatly contribute to identifying the pathogenesis of thyroid cancer in children and increasing treatment efficiency through targeted treatment based on genetic mutations.

Story source: Seoul National University Press Release
Journal Reference: Lee YA, Lee H, Im SW, Song YS, Oh DY, Kang HJ, Won JK, Jung KC, Kwon D, Chung EJ, Hah JH, Paeng JC, Kim JH, Choi J, Kim OH, Oh JM, Ahn BC, Wirth LJ, Shin CH, K doi: 10.1172/JCI144847. PMID: 34237031; PMCID: PMC8439610.

Categories: Clinical, Journals