Dissecting the genetic drivers of thyroid cancer metastization

Valdemar Máximo, Arnaud Da Cruz Paula and Paula Soares from the Cancer Signaling & Metabolism group at i3S have always wanted to know more about the genomic profiling of primary and metastatic thyroid cancers. Hence, they decided to meticulously characterize the genomic features of these neoplasms.

Thyroid cancer (TC) is the most frequent endocrine malignancy. While the genetic repertoire of primary TCs has been well documented in recent years, the molecular profiling of the metastases remains rather poor, being the metastatic disease what impacts more patient prognosis. With this issue in mind, the authors retrieved the molecular and clinical features of primary TCs and unmatched metastases of various histologic types from the cBioPortal database, and provided a characterization of the repertoire of somatic mutations and copy number alterations.

The genetic repertoire of papillary thyroid carcinomas (PTCs) revealed a significantly higher frequency of TERT promoter mutations in the metastases than in primary tumors, “confirming that these mutations are strongly associated with tumor progression” said Paula Soares. Additional genetic alterations were observed in the metastases from PTCs, such as those affecting CDKN2A. “The poor clinical outcome obtained in our study for patients harboring CDKN2A pathogenic alterations, suggests that this gene may be regarded as an additional prognostic factor for patients with advanced PTCs.”

In addition, they found that RET translocations were significantly more frequent in metastases from PTCs than in primary tumors, and that patients harboring such translocations have a poor overall survival. “Given the presence of highly specific small-molecule RET inhibitors, it is crucial to better understand the natural history of patients with RET-rearranged TCs.” advance Valdemar Máximo.

They also observe a significantly lower frequency of BRAF hotspot mutations in the distant metastases (DMs) than in lymph node metastases from PTCs. A plausible explanation for such observation may rely in “the fact that other driving events, such as TERT promoter mutations, RET translocations or CDKN2A homozygous deletions are more linked to DMs, highlighting the importance of gene fusion and copy number alterations in predicting DMs.”, suggests Arnaud Da Cruz Paula.

A high frequency of NF1 biallelic loss in metastatic Hurthle cell carcinomas (HCCs) was observed, thus highlighting the role of loss of NF1 in the progression of HCCs. They also noticed a high frequency of TP53 biallelic alterations in the metastases from poorly differentiated thyroid carcinomas (PDTCs). In fact, these genetic alterations were previously shown to occur late in the progression of TCs, with increasing incidence from differentiated to poorly differentiated, to anaplastic thyroid carcinomas (ATCs). Hence, “TP53 genetic alterations may predict which tumors will be triggered by dedifferentiation and evolution to ATCs.” says Paula Soares.

“Potential targets such as RET translocations and BRAF hotspot mutations were found to be enriched in metastatic PTCs, PDTCs and ATCs (as well as NF1 biallelic losses, which were found to be enriched in metastatic HCCs) that may be explored therapeutically.”, concluded Valdemar Máximo.

Authors and Affiliations:

Valdemar Máximo^1,2,3, Miguel Melo^1,2,3,4, Yingjie Zhu⁵, Andrea Gazzo⁵, Manuel Sobrinho Simões^1,2,3,6, Arnaud Da Cruz Paula^1,2*, Paula Soares^1,2,3*

¹i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal;

²Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal;

³Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto 4200-319, Portugal;

⁴Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Medical Faculty, University of Coimbra, Portugal;

⁵Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; ⁶Department of Pathology, Hospital São João, Porto 4200-319, Portugal

Abstract:

The genetic repertoire of primary thyroid cancers (TCs) is well documented, but there is a considerable lack of molecular profiling in metastatic TCs. Here, we retrieved and analyzed the molecular and clinical features of 475 primary and metastatic TCs subjected to targeted DNA sequencing, from the cBioPortal database. The cohort included primary and metastatic samples from 276 papillary thyroid carcinomas (PTCs), 5 follicular thyroid carcinomas, 22 Hürthle cell carcinomas (HCCs), 127 poorly differentiated thyroid carcinomas (PDTCs), 30 anaplastic thyroid carcinomas (ATCs) and 15 medullary thyroid carcinomas. The ATCs had the highest tumor mutational burden and the HCCs the highest fraction of the genome altered. Compared to primary PTCs, the metastases had a significantly higher frequency of genetic alterations affecting TERT (51% vs 77%, P < 0.001), CDKN2A (2% vs 10%, P < 0.01), RET (2% vs 7%, P < 0.05), CDKN2B (1% vs 6%, P < 0.05) and BCOR (0% vs 4%, P < 0.05). The distant metastases had a significantly lower frequency of BRAF (64% vs 85%, P < 0.01) and a significantly higher frequency of NRAS (13% vs 3%, P < 0.05) hotspot mutations than the lymph node metastases. Metastases from HCCs and PDTCs were found to be enriched for NF1 (29%) and TP53 (18%) biallelic alterations, respectively. The frequency of subclonal mutations in ATCs was significantly higher than in PTCs (43% vs 25%, P < 0.01) and PDTCs (43% vs 22%, P < 0.01). Metastatic TCs are enriched in clinically informative genetic alterations such as RET translocations, BRAF hotspot mutations and NF1 biallelic losses that may be explored therapeutically.

Journal: Endocrine-Related Cancer

Link: https://erc.bioscientifica.com/view/journals/erc/31/2/ERC-23-0144.xml