Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer

Abstract

Background: Distant metastasis is a rare occurrence in thyroid cancer, and it can be associated with poor prognosis. The genomic repertoires of various solid malignancies have previously been reported but remain underexplored in metastatic papillary thyroid cancer (PTC). Furthermore, whether distant metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. Methods: We performed whole-exome sequencing on 14 matched distant metastases, primary PTC tumors, and normal tissues. Point mutations, copy number alterations, cancer cell fractions, and mutational signatures were defined using the state-of-the-art bioinformatics methods. All likely deleterious variants were validated by orthogonal methods. Results: Genomic differences were observed between primary and distant metastatic deposits, with a median of 62% (range 21-92%) of somatic mutations detected in metastatic tissues, but absent from the corresponding primary tumor sample. Mutations in known driver genes including BRAF, NRAS, and HRAS were shared and preferentially clonal in both sites. However, likely deleterious variants affecting DNA methylation and transcriptional repression signaling genes including SIN3A, RBBP1, and CHD4 were found to be restricted in the metastatic lesions. Moreover, a mutational signature shift was observed between the mutations that are specific or enriched in the metastatic and primary lesions. Conclusions: Primary PTC and distant metastases differ in their range of somatic alterations. Genomic analysis of distant metastases provides an opportunity to identify potentially clinically informative alterations not detected in primary tumors, which might influence decisions for personalized therapy in PTC patients with distant metastasis.

Intratumoral Genetic Heterogeneity in Papillary Thyroid Cancer: Occurrence and Clinical Significance

“…A discordant mutational status between the primary site and the metastases supports this mechanism and it was recorded in several human tumors (including lung, melanoma, colorectal, gastric, breast) [4]. In TC, discordant patterns were reported for BRAF V600E , TERT, RAS and other mutations [27,39,40,51,52,[58][59][60][61][62][63][64][65]. Data related to PTC are reviewed in Table 3.…”

“…Interestingly, the two selected areas of the primary tumor and the two selected areas of on regional metastasis presented similar genetic profiles, whereas the two selected areas of another regional metastasis had more divergent mutations and fusions [55]. Striking heterogeneity was also observed between paired primary tumors and metastases in studies done by means of NGS and WES studies [58,60,63,64]. Mass spectrometry imaging lymph node discordant Gawin et al 2019 [65] Legend: * for likely pathogenic cancer genes.…”

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

“…used whole-exome sequencing to compare 14 trios of matched distant metastasis, primary PTC tumors and normal samples. Those authors found striking heterogeneity between the primary PTC tumors and metastatic specimens, attributed mainly to passenger mutations ( 19 ). In comparison to those studies, our study population is more heterogeneous and reflects real life practice in a tertiary hospital.…”

“…Only a few studies have addressed this question, employing different approaches and reaching diverse conclusions ( 16 – 19 ).…”

Differences in Gene Expression Profile of Primary Tumors in Metastatic and Non-Metastatic Papillary Thyroid Carcinoma—Do They Exist?

“…In previous attempts, we succeeded in deriving novel markers for follicular thyroid tumors, in samples analyzed previously by microarray and qPCR [62,63]. It also cannot be excluded that metastatic spread in certain tumors is a stochastic event, or the changes are late and discriminable only when distant metastasis tissue is accessible [64]. In any of these scenarios, we cannot abandon the approaches to search for molecular predictors, as the clinically known PTC features are not sufficient to predict patient outcome in full [7].…”