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. 2021 Feb 25:12:623182.
doi: 10.3389/fendo.2021.623182. eCollection 2021.

Do Molecular Profiles of Primary Versus Metastatic Radioiodine Refractory Differentiated Thyroid Cancer Differ?

Cristiane J Gomes-Lima  1   2   3 , Leila Shobab  2 , Di Wu  1   2 , Dorina Ylli  1   2 , Athanasios Bikas  4 , Matthew McCoy  5 , Rebecca Feldman  6 , Wen Lee  4 , Sarika N Rao  7 , Kirk Jensen  8 , Vasily Vasko  8 , Luiz Claudio Castro  9 , Jacqueline Jonklaas  10 , Leonard Wartofsky  1   2 , Kenneth D Burman  2
Affiliations

Do Molecular Profiles of Primary Versus Metastatic Radioiodine Refractory Differentiated Thyroid Cancer Differ?

Cristiane J Gomes-Lima et al. Front Endocrinol (Lausanne). .

Abstract

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25-82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF, NRAS, HRAS, TP53, ATM, MUTYH, POLE, and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

Keywords: differentiated thyroid cancer; metastases; molecular profile; next generation sequencing; radioiodine refractory.

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Conflict of interest statement

RF is employed by Caris Life Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Genetic landscape and immunohistochemistry (PD-L1 expression) of paired sites. Each column represents one subject. The upper part of the figure refers to aspects of primary tumors and the bottom, to metastatic sites specified in the figure. *means quality or quantity not sufficient for analysis. PTC, papillary thyroid cancer; FVPTC, follicular variant of papillary thyroid cancer; CPTC, columnar variant of papillary thyroid cancer; FTC, follicular thyroid cancer; HTC, Hürthle cell thyroid cancer; IHC, immunohistochemistry; TMB, tumor mutation burden; Mb, megabase; MSI, microsatellite instability; RAI, radioiodine; LN, lymph node.
Figure 2
Figure 2
Functional network among cancer driver genes identified in this cohort and genes highly expressed in the thyroid. Nodes represent proteins, edges show functional associations and line thickness corresponds to the strength of the supporting evidence. ATM, ATM serine/threonine kinase; BRAF, B-Raf proto-oncogene,serine/threonine kinase; CALCB, Calcitonin Related Polypeptide Beta; FOXE1, Forkhead Box E1; HRAS, HRas Proto-Oncogene, GTPase; IYD, Iodotyrosine Deiodinase; MUTYH, MutY DNA Glycosylase; NRAS, NRAS Proto-Oncogene, GTPase; NTR, Nerve Growth Factor Receptor; NTRK1, Neurotrophic Receptor Tyrosine Kinase 1; NTRK3, Neurotrophic Receptor Tyrosine Kinase 3; OTOS, Otospiralin; PAX8, Paired Box 8; PDE8B, Phosphodiesterase 8B; POLE, DNA Polymerase Epsilon, Catalytic Subunit; RAG2, Recombination Activating 2; SLC26A4, Solute Carrier Family 26 Member 4; TG, Thyroglobulin; TP53, Tumor Protein P53; TPO, Thyroid Peroxidase; TSHR, Thyroid Stimulating Hormone Receptor.
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