Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis

Abstract

Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene-panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p < 0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

Telomerase reverse transcriptase mutations are independent predictor of disease‐free survival in Middle Eastern papillary thyroid cancer

“…Strikingly, the frequency of TERT mutations was much higher in this subgroup (73.7%) than in the overall cohort ( p < 0.0001) (Figure C ). As we have previously highlighted the role of thyroglobulin ( TG ) gene mutations in distance metastasis, we performed the previous analysis with and without TG mutations positive cases and the significance of these results stands true even without TG mutations cases which further highlights the independent role of TERT mutation in malignant evolution of PTC (Supporting Information, Figure 1).…”

“…We then asked whether this survival effect was independently driven by TERT mutations rather than coexisting driver mutations because in our previous study, BRAF mutations were seen in 60.0% of our PTC cases . In this study, 69.5% (116/167) of TERT mutation‐positive PTC samples had coexisting BRAF mutations.…”

The Profile of Genetic Mutations in Papillary Thyroid Cancer Detected by Whole Exome Sequencing

“…For example, in the study of Siraj AK et al, they suggested a previously unknown role of thyroglobulin (TG) somatic mutations in the pathogenesis of PTC [26]. Pan et al found a exome mutational spectrum of PTC in the Chinese population and highlights lncRNA GAS8-AS1 and LPAR4 as potential diagnostic and therapeutic targets [27].…”

Thyroglobulin in Metastatic Thyroid Cancer: Culprit or Red Herring?

“…The need for further validation is supported by the authors' finding that the majority of TG mutations (21/27) co-existed with mutations in RAS/MAPK signaling pathway genes. However, Kaplan-Meier survival plots revealed worse survival of individuals with TG-mutated tumors than of those with wild-type TG and worse survival of individuals with mutations in TG and MAPK pathway genes than of MAPK-mutation-positive tumors alone (Figure 3 in Siraj et al 1 ). Because the majority of TG-mutated tumors also harbor MAPK mutations, it is rather difficult to ascertain the contribution of TG somatic mutations on survival, especially given that MAPK mutations, such as in BRAF, have also been associated with aggressive disease and poorer survival, so noted by the authors.…”

“…11 It would also be crucial to ensure deep sequencing at the primary PTC tissues given that the reported mutation site ( Figure S4 in Siraj et al 1 ) seems to show multiple mutated bases at the same spot (hence controlling for sequencing noise). Ultimately, further functional investigation is necessary to support the important findings by Siraj et al and to ascertain the role of TG somatic mutations in aggressive and metastatic PTC.…”