Early Detection of Relapse by ctDNA Sequencing in a Patient with Metastatic Thymic Tumor and MEN1 Mosaicism

Abstract

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease due to inactivating mutations in the MEN1 gene. In the literature, few cases of MEN1 have been reported due to mosaic MEN1 mutations. Objective: We performed an extensive molecular characterization in several lesions and blood samples, including plasmatic circulating cell-free DNA (ccfDNA) in an exceptional case of a patient with MEN1 mosaicism causing primary hyperparathyroidism, multiple pancreatic neuroendocrine tumors (NET), and a metastatic thymic NET. Design Blood, ccfDNA and multiple tissue analysis were performed by next generation sequencing. Results MEN1 mosaicism was confirmed by the multiple tissues analysis. The somatic analysis of the largest pancreatic NET revealed the same MEN1 second-hit mutation as found in thymic lesion, demonstrating its metastatic origin from thymic lesion. Moreover, in ccfDNA we found the mosaic MEN1 mutation but also the somatic second-hit mutation found in the thymic primary tumor, revealing the presence of circulating tumor DNA (ctDNA). After surgical removal of the pancreatic metastasis, the mutated fraction of both mutations decreased, before increasing again several weeks before a new clinical relapse, suggesting that thymic ctDNA may be used as an early tumor biomarker. Conclusion This exceptional MEN1 case highlighted (1) the importance of looking for MEN1 mosaicism (2) that MEN1 mosaicism can cause very aggressive disease, (3) the interest in analyzing ccfDNA for confirming MEN1 mosaicism but also a potential tumor biomarker for NET.

Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors

“…Additional markers could play a significant role in both diagnostic and therapeutic strategies [ 82 , 83 ]. Moreover, studies have assessed the plasmatic circulating cell-free DNA (ccfDNA) in patients with MEN1 or VHL [ 123 , 124 ]. A case study of a patient with MEN1 mosaicism showed that ccfDNA from thymic variants were detected a month before the relapse of TNET, showing that the TNET was growing, and ccfDNA was suggested as a potential early tumor marker [ 123 ].…”

“…Moreover, studies have assessed the plasmatic circulating cell-free DNA (ccfDNA) in patients with MEN1 or VHL [ 123 , 124 ]. A case study of a patient with MEN1 mosaicism showed that ccfDNA from thymic variants were detected a month before the relapse of TNET, showing that the TNET was growing, and ccfDNA was suggested as a potential early tumor marker [ 123 ]. In another case study with metastatic clear renal cell carcinoma, ccfDNA was investigated, and changes in variant allele frequency (VAF) of VHL mutation were associated with the tumor size assessed by radiographic images [ 124 ].…”

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance

“…MEN1 (Wermer’s syndrome), an autosomal dominantly inherited syndrome with an increased penetrance, displays a poor genotype/phenotype correlation, a variation that has been hypothesized to be the effect of the “double hit hypothesis” and of a large spectrum of exogenous and endogenous factors (including epigenetic elements such as microRNAs [ 66 ] that were identified in both pancreatic and parathyroid cells) [ 67 , 68 , 69 , 70 , 71 ]. Heterozygote-inactivating pathogenic variants of the MEN1 tumor suppressor gene (chromosome11q13) encoding the MENIN protein are followed by the somatic loss of the heterozygosity of the MEN1 gene at the level of neuroendocrine cells [ 72 , 73 ]. The condition has a familial pattern in nine out of ten cases, while one out of ten subjects with MEN1 shows de novo mutations; thus, the early recognition and prompt introduction of surveillance protocols in this particular instance might not be feasible in daily practice [ 74 , 75 ].…”

“…At a lower level of statistical evidence, we mention the sample-focused analysis of case reports with regard to the parathyroid and pancreatic MEN1-NETs having a specified genetic confirmation of the MEN1 pathogenic variant (regardless of if the type was detailed by the original authors) [ 68 , 73 , 75 , 77 , 81 , 97 , 100 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ] ( Table 6 ).…”

“…There were 24 MEN1 subjects (including index cases with genetic analysis for their relatives) within 24 papers; they were aged between 17 years (only two pediatric cases were found) and 74 years; the female-to-male ratio was 0.84. The female population (N = 11) had an average age of 43.63 years (ranges between 28 and 60); males (N = 13) had a mean age of 40.07 years (ranges between 17 and 74) [ 68 , 73 , 75 , 77 , 81 , 97 , 100 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ].…”