Cancers (Basel). 2020;12(5):cancers12051345.

Genomic and Transcriptomic Characteristics According to Size of Papillary Thyroid Microcarcinoma.

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제1저자 송영신 · 교신저자 박영주

PMID 32466217 PMC7281223 DOI 10.3390/cancers12051345 IF 4.8 내분비대사내과

소속 (11)

Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea.
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul 03080, Korea.
Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Internal Medicine, Kosin University College of Medicine, Busan 49267, Korea.
Data Labs, SK Telecom, Seoul 04539, Korea.
Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea.
Macrogen Inc., Seoul 08511, Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.
Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea.

Abstract

It is controversial as to whether papillary thyroid microcarcinoma (PTMC) has some genomic and transcriptomic characteristics that differentiate between an early-stage lesion that would eventually evolve into the larger papillary thyroid cancer (PTC), and an occult indolent cancer in itself. To investigate this, we comprehensively elucidated the genomic and transcriptomic landscapes of PTMCs of different sizes, using a large-scaled database. This study included 3435 PTCs, 1985 of which were PTMCs. We performed targeted next-generation sequencing for 221 PTCs and integrated these data with the data including The Cancer Genome Atlas (TCGA) project. The frequency of v-raf murine sarcoma viral oncogene homolog B (BRAF)^V600E mutation was higher in PTMCs >0.5 cm than that in very small PTMCs (≤0.5 cm) and decreased again in PTCs >2 cm. Among PTMCs, the prevalence of mutations in rat sarcoma (RAS) and telomerase reverse transcriptase (TERT) promoter was not significantly different according to their size, but lower than in large PTCs. There was no change in the tumor mutational burden, the number of driver mutations, and transcriptomic profiles with tumor size, among PTMCs and all PTCs. Although a few genes with differential expression and TERT promoter mutations were found in a few PTMCs, our findings showed that there were no useful genomic or transcriptomic characteristics for the prediction of the future progression of PTMC.

Keywords

genomemassively parallel sequencingmolecular characteristicspapillary thyroid microcarcinomatranscriptometumor size

Figures

**Figure 1** Genomic characteristics of papillary thyroid carcinoma according to tumor size. Prevalence of *BRAF*^V600E and *RAS* mutations according to tumor size in (A) classical (n = 2954 and 851 for *BRAF*^V600E and *RAS*, respectively) and (B) follicular variant (n = 342 and 217 for *BRAF*^V600E and *RAS*, respectively) PTCs. Prevalence of *TERT* promoter mutations (*TERT* alone, *TERT* + *BRAF*, and *TERT* + *RAS*) according to tumor size in (C) classical (n = 707) and (D) follicular variant (n = 184) PTCs. (E) Tumor mutational burden, (F) number of driver mutations, and (G) proportions of non-silent mutations involved in mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and (H) in phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathways compared to total non-silent mutations, according to tumor size of PTC in the SNUH targeted sequencing (SNUH-TS, n = 221) and TCGA (n = 496) datasets. cPTC, classical papillary thyroid carcinoma; fvPTC, follicular-variant papillary thyroid carcinoma; PTMC, papillary thyroid microcarcinoma; PTC, papillary thyroid carcinoma.

**Figure 2** Transcriptomic characteristics of papillary thyroid microcarcinoma. Principal component analysis plot of PTC from the (A) SNUH RNA-sequencing (SNUH-RS, n = 124) and (B) TCGA (n = 496) datasets. Volcano plots showing differential RNA expression levels between PTMC and PTC >1 cm in all PTCs (left), *BRAF* mutant PTCs (middle), and *RAS* mutant PTCs (right) from the (C) SNUH-RS (n = 43 vs. 81, 29 vs. 37, 4 vs. 20, respectively) and (D) TCGA (n = 39 vs. 457, 18 vs. 217, 3 vs. 49, respectively) datasets. Up- and down-regulated DEGs in PTC >1 cm compared to PTMC are marked in dark red and dark green, respectively. PTMC, papillary thyroid microcarcinoma; PTC, papillary thyroid carcinoma.

**Figure 3** Transcriptomic characteristics of papillary thyroid microcarcinoma according to tumor size. Volcano plots showing differential RNA expression levels between groups of all PTMCs: ≤0.6 cm vs. >0.6 cm (left), ≤0.7 cm vs. >0.7 cm (middle), and ≤0.8 cm vs. >0.8 cm (right) from the (A) SNUH RNA-sequencing (SNUH-RS, n = 13 vs. 30, 22 vs. 21, 32 vs. 11, respectively) and (B) TCGA (n = 9 vs. 30, 14 vs. 25, 17 vs. 22, respectively) datasets. (C) *TERT* mRNA expression levels according to tumor size (upper graph) from both datasets. Each column represents an individual sample. The number of cases with *TERT* mRNA expression according to tumor size (lower table). Thyroid differentiation score (D) and ERK score (E) according to tumor size from both datasets (n = 124 and 496 for SNUH-RS and TCGA datasets, respectively). PTMC, papillary thyroid microcarcinoma.

그림 출처: PubMed Central 공개 논문 (PMC7281223)

Conflict of interest statement

The authors declare no conflict of interest.

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