Article révisé par les pairs
Résumé : The contribution of intratumor heterogeneity to thyroid metastatic cancers is still unknown. The clonal relations between the primary thyroid tumors and lymph nodes (LN) or distant metastases are also poorly understood. The objective of this study was to determine the phylogenetic relationships between matched primary thyroid tumor and metastases. We searched for non-synonymous single nucleotide variants (nsSNVs), gene fusions, alternative transcripts and loss of heterozygosity (LOH) by paired-end massively parallel sequencing of cDNA (RNA-Seq) in a patient diagnosed with an aggressive papillary thyroid cancer (PTC). Seven tumor samples of a stage IVc PTC patient were analyzed by RNA-Seq: two foci from the primary tumor, four foci from two LN metastases and one focus from a pleural metastasis. A large panel of other thyroid tumors was used for Sanger sequencing screening. We identified seven new nsSNVs. Some of these were early events clonally present in both the primary PTC and the three matched metastases. Other nsSNVs were private to the primary tumor, the LN metastases and/or the pleural metastasis. Three new gene fusions were identified. A novel cancer-specific KAZN alternative transcript was detected in this aggressive PTC and in dozens of additional thyroid tumors. The pleural metastasis harbored an exclusive whole chromosome 19 LOH. We presented the first deep sequencing study comparing the mutational spectra in a PTC and both LN and distant metastases. This study provides novel findings concerning intra-tumor heterogeneity, clonal evolution and metastases dissemination in thyroid cancer.

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