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The genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis

Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland with arelatively high cure rate. Distant metastasis (DM) of PTC is uncommon, but when it occurs, itsignificantly decreases the survival of PTC patients. However, the molecular mechanisms of DMin PTCs have not been systematically studied. We performed whole exome sequencing andGeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched whiteblood cell samples from 20 PTCs with DM and 46 PTCs without DM. We identified somaticmutations, gene fusions and copy number alterations and analyzed their relationships with DM ofPTCs. BRAF-V600E was identified in 73% of PTCs, followed by RET fusions (14%) in a mutuallyexclusive manner (p<0.0001). We found gene fusions (RET, ALK or NTRK1) (p<0.01) andchromosome 22q loss(p<0.01) were independently associated with DM by both univariate andmultivariate analysis. A nomogram model consisting of chromosome 22q loss, gene fusions andthree clinical variables was built for predicting DM in PTC (C-index=0.89).The plasma circulatingtumor DNA (ctDNA) detection rate in PTCs was only 38.9%, however, it was significantlyassociated with the metastatic status (p= 0.04), tumor size (p= 0.001) and invasiveness (p= 0.01).In conclusion, gene fusions and chromosome 22q loss were independently associated with DM inPTCs and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate waslow in non-DM PTCs but significantly higher in PTCs with DM.