Abstract 2073: Exome sequencing reveals PTPRS, NOTCH3, FGFR1/3 mutations as novel mutational features in medullary thyroid cancer
Authors: Boateng Isaiah , Yilmaz Ayse S. , Brock Pamela , Liyanarachchi Sandya , Patel Ravi , Walker Christopher J. , Phay John , de la Chapelle Albert , Ringel Matthew , Eisfeld Ann-Kathrin 
Published: September 2020

Abstract
Background: Approximately 1,000 patients are diagnosed with medullary thyroid cancer (MTC) in the United States each year; a tumor type that disproportionately causes thyroid cancer-related death. The molecular hallmark of MTC are mutations of the Rearranged During Transfection (RET) proto-oncogene: ~25% of MTC patients harbor germline RET variants and somatic RET mutations can be found in ~ 40% of sporadic medullary thyroid cancers. However, with the exception of RAS mutations relatively little is known of the broad molecular landscape of MTC.
Material & Methods: To further explore the mutational features of MTC, we performed whole exome sequencing on paired tumor and normal tissue on a cohort of 14 patients with MTC. For variant calling, we focused on the 468 genes included in the MSK-IMPACT panel. Paired RNA sequencing was available for 7 patients. A variant was included as potential pathogenic based on a combination of SIFT, Polyphen and clinical significance prediction. Only coding variants were considered.
Results: Out of the 14 patients, 43% were female (n=6), and 57% (n=8) were male (Table 1). The median age was 55.5 years (range: 21-79 years). At time of diagnosis, 29% had stage I (n=4), 14% stage II (n=2), 21% stage III (n=3), and 36% (n=5) had stage IV disease. The majority of patients (71%, n=10) had multifocal disease. While half of the patients had lymphovascular tumor invasion (50%, n=7), only 14% (n=2) had capsular invasion. Of all patients, 29% (n=4) of patients were germline RET mutation carriers. In our somatic tumor profiling, we detected a total of 23 potential pathogenic variants. The median mutation burden per patient was 2 (range= 0-7). Three patients had no detectable mutations. Expectedly, mutations in the RET gene were also the most frequent somatic mutational events and were detected in 43% (n=6) patients. Interestingly, we identified recurrent mutations in 3 genes that to the best of our knowledge have not been previously described in MTC. Protein- Tyrosine phosphate receptor-type sigma (PTPRS), Notch receptor 3 (NOTCH3), and Fibroblast growth factor receptors1/3 (FGFR1/3). Each of these was mutated in 21% (n=2) MTC patients. In addition, 10 genes were found mutated in a single MTC patient (CHEK2, DNMT1, EP300, GNAS, KMT2A, PIK3C2G, PNRC1, POLE, PRKAR1A, SOX2). In the RET wildtype patients, DNMT1, FGFR1, KMT2A, PIK3C2G, PRKAR1A and PTPRS were the only detected lesions, suggesting a possible pathophysiological importance independent of RET.
Conclusions: Our exome sequencing study identified recurrent mutations in PTPRS, NOTCH3, FGFR1/3 as novel recurrent mutational features in MTC. Notably, some of them were detected in RET wildtype patients, suggesting a possible functional role of the genes in carcinogenesis. The functional studies to further define the roles of these gene mutations in MTC are ongoing.
Citation Format: Isaiah Boateng, Ayse S. Yilmaz, Pamela Brock, Sandya Liyanarachchi, Ravi Patel, Christopher J. Walker, John Phay, Albert de la Chapelle, Matthew Ringel, Ann-Kathrin Eisfeld. Exome sequencing reveals PTPRS, NOTCH3, FGFR1/3 mutations as novel mutational features in medullary thyroid cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2073.