Abstract 2770: Spatio-temporal genetic heterogeneity and clonal evolution in advanced papillary thyroid carcinomas and matched distant metastases

Abstract

Abstract Papillary Thyroid Carcinoma (PTC) represents 65-80% of all thyroid cancers. Though the vast majority of PTCs are indolent tumors, around 5-15% behave aggressively, developing blood-borne metastases, which cause patient's death. The molecular mechanisms underlying metastatic spread are poorly understood. Little it is known about the contribution of intratumor molecular heterogeneity to distant metastases (DM). Dynamic changes in mutation distribution through space and time have not been in deep characterized. In this study, by genotyping 13 cases of matched primary tumors (PrT) and DMs, we sought to determine the prevalence of mutations in genes that have been associated with tumor progression and aggressiveness in follicular thyroid carcinogenesis (TERTp, MED12, BRAF, NRAS, KRAS, HRAS, PIK3CA). To asses the contribution of intratumor heterogeneity and clonal evolution to DMs, 54 tumor areas, including different areas across space and time within the PrTs and the DMs were characterized. Mutational analysis was approached by means of PCR and SSCP or direct sequencing. Twelve cases (92%) were mutated in at least one of the genes screened [TERTp=9 cases (69%), BRAF=7 cases (54%), KRAS=3 cases (23%), NRAS=3 cases (23%), HRAS=2 cases (15.4%) and PIK3CA=2 cases (15.4%)]. No mutations were seen at MED12. Among the mutated cases 67% exhibited more than 1 gene activated. Three mutated genes co-existed in 62.5% of the cases with concomitant mutations [3 cases (60%) TERTp+RAS+BRAF and 2 cases (40%) TERTp+BRAF+PIK3CA]. Concurrent activation of TERTp+RAS or TERTp+BRAF was seen in 5 cases each event (62.5%). Simultaneous activation of BRAF and RAS was found in 4 cases (50%). In all the cases in which more than 1 area of DM, across space and time, was analyzed, the mutations at TERTp, KRAS and HRAS resulted clonal. De novo mutations at DM, not present in the PrT, were seen in 3 cases mutated at TERTp, 2 cases mutated at NRAS, 1 case mutated at KRAS. Among the mutated cases, in which more than one area of PrT was analyzed, clonality was seen in 80% of the cases mutated at TERTp and subclonality was seen in 80% of the cases mutated at BRAF. The activation of RAS within the PrT tend to be a clonal event. Conclusions: The number of mutational events in PTC with DM is strikingly higher than in in PTC without DM. While TERTp and RAS mutations tend to be clonal within the PrT and the DMs, BRAF mutations tend to be subconal. TERTp and RAS mutations may appear the novo at DM. PTC with DM display a much higher rate of genetic heterogeneity (67%). The coexistence of mutations in different genes is in agreement with the hypothesis that tumor progression relies on progressive accumulation of genetic alterations. MED12 does not play a role in aggressive papillary thyroid carcinomas. Concurrent mutations at TERTp, and different PI3K/AKt and MAPK pathway genes are common in poorly differentiated and anaplastic carcinomas. Note: This abstract was not presented at the meeting. Citation Format: Sara Gil-Bernabe, Noa Feas Rodríguez, Miriam Vega Herrero, Jose Javier Estébanez García, Ginesa M. Garcia-Rostan. Spatio-temporal genetic heterogeneity and clonal evolution in advanced papillary thyroid carcinomas and matched distant metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2770.