Abstract 6069: Genomic and transcriptomic characterization of medullary thyroid cancer

Abstract Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy derived from the parafollicular C cells of thyroid gland. It features relatively aggressive biologic behavior among thyroid cancers, but its genomic landscape has not yet been fully explored. Here, we conducted multi-omics data (whole genome sequencing (WGS), and bulk (bulk RNA-seq) or single nucleus RNA sequencing (snRNA-seq)) on ​​MTC, and found genetic characteristics of MTC and a new gene signature predicting aggressiveness of tumors. WGS was performed for 35 pairs of tumor specimens and normal thyroid tissues from 30 patients. And bulk RNA-seq for 59 samples (20 normal thyroid tissues, 26 primary MTCs, 9 recurred lymph nodes, and 4 metastatic lymph nodes) and snRNA-seq for 3 primary MTCs, and 2 recurred/metastatic lymph nodes were also performed. In WGS results, we verified driver mutations, including RET, RAS, and BRAF. Four patients were classified as germline RET mutations based on familial history. Somatic RET M918T mutations were occurred in 8 patients, 9 patients were observed other RET mutations. Also, we observed other somatic mutations such as HRAS and BRAF. Seven patients occurred somatic HRAS mutations (Q61L, Q61R, G13R, A11 and G15), and somatic BRAF mutations (G469A, K601E) were observed in two patients. We found broad-level copy-number alterations in ~50% of patients, and we also found a patient who shows whole-genome duplication. The copy-number alteration was associated with aggressive phenotype in MTC. In addition, we found complex rearrangements such as microhomology-mediated break-induced replication in five patients. Interestingly, we found intra-tumoral heterogeneity of several genes related to C cell differentiation through snRNA-seq analysis by comparing clusters of tumor cells. Using the genes, we calculated the C cell differentiation score of the samples with bulk RNA-seq by GSVA algorithm. This score was related to poor clinical characteristics such as recurrence. In conclusion, multi-omics profiling of MTC reveals that copy number alterations and C cell differentiation status are the important biomarkers for cancer aggressiveness. Citation Format: Seong Eun Lee, Seongyeol Park, Shinae Yi, Joonoh Lim, Na Rae Choi, JungHak Kwak, June-Young Koh, Boram Yi, Jaemo Koo, Jae Won Chang, Young Seok Ju, Bon Seok Koo, Jin Man Kim, Young Joo Park, Minho Shong, Eun Kyung Lee, Jae Kyung Won, Yea Eun Kang, Kyu Eun Lee. Genomic and transcriptomic characterization of medullary thyroid cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6069.